429 results on '"J.-C. Schwartz"'
Search Results
2. Pitolisant long term effect in sleepy obstructive sleep apnea patients without CPAP
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Y. Dauvilliers, J. Verbraecken, M. Partinen, J. Hedner, T. Saaresranta, O. Georgiev, R. Tiholov, I. Lecomte, R. Tamisier, P. Lévy, J.-M. Lecomte, J.-C. Schwartz, and J.-L. Pépin
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General Medicine - Published
- 2022
3. Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies
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Pierre Maison-Blanche, Xavier Ligneau, Jean-François Faivre, J C Schwartz, Gary R. Mirams, Jeanne-Marie Lecomte, Rashmi R. Shah, Isabelle Berrebi-Bertrand, Laurent Landais, and Philippe Robert
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0301 basic medicine ,Pharmacology ,Proarrhythmia ,Cardiovascular safety ,Pitolisant ,biology ,business.industry ,hERG ,Dofetilide ,030204 cardiovascular system & hematology ,medicine.disease ,In vitro ,3. Good health ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,In vivo ,biology.protein ,Medicine ,Ventricular myocytes ,business ,medicine.drug - Abstract
Background and purpose: We evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant. Experimental approach: Nonclinical studies envisaged both in the ICH S7B guideline and Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative were undertaken. CiPA-initiative studies included in vitro ion channels and stem cell-derived human ventricular myocyte studies as well as in silico modelling of results to simulate human ventricular electrophysiology. ICH S7B-recommended studies included in vitro hERG studies, in vivo dog study with follow-up investigations in rabbit Purkinje fibres and in vivo studies in the Carlsson rabbit proarrhythmia model. Key results: Both sets of nonclinical studies consistently excluded pitolisant from having clinically relevant QT-liability or proarrhythmic potential. CiPA studies revealed pitolisant to have modest calcium channel blocking and late I Na reducing activities at high concentrations, which resulted in reduction of dofetilide-induced early after-depolarisations (EADs) by pitolisantin ICH S7B studies. Studies in stem cell-derived human cardiomyocytes with dofetilide or E-4031 given alone and in combination with pitolisant confirmed these properties. In silico modelling confirmed that the measured ion channel effects are consistent with results from both the stem cell-derived cardiomyocyte and rabbit Purkinje fibre studies and categorised pitolisant as a drug with low torsadogenic potential. The results from the two sets of nonclinical studies correlated well with two clinical QT studies. Conclusions and implications: Our experience supports the CiPA initiative but suggests that sponsors should consider investigating drug effects on EADs and the use of proarrhythmia models when the results from CiPA studies are ambiguous.
- Published
- 2017
4. Preclinical evaluation of the abuse potential of Pitolisant, a histamine H3receptor inverse agonist/antagonist compared with Modafinil
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M Uguen, PM Beardsley, Xavier Ligneau, Jeanne-Marie Lecomte, Perrin David, S Belliard, and J.-C. Schwartz
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Pharmacology ,Pitolisant ,Dopaminergic ,Modafinil ,Physical dependence ,Nucleus accumbens ,Conditioned place preference ,chemistry.chemical_compound ,chemistry ,Dopamine ,medicine ,Inverse agonist ,medicine.symptom ,Psychology ,medicine.drug - Abstract
Background and Purpose Pitolisant, a histamine H3 receptor inverse agonist/antagonist is currently under Phase III clinical trials for treatment of excessive daytime sleepiness namely in narcoleptic patients. Its drug abuse potential was investigated using in vivo models in rodents and monkeys and compared with those of Modafinil, a psychostimulant currently used in the same indications. Experimental Approach Effects of Pitolisant on dopamine release in the nucleus accumbens, on spontaneous and cocaine-induced locomotion, locomotor sensitization were monitored. It was also tested in three standard drug abuse tests i.e. conditioned place preference in rats, self-administration in monkeys and cocaine discrimination in mice as well as in a physical dependence model. Key Results Pitolisant did not elicit any significant changes in dopaminergic indices in rat nucleus accumbens whereas Modafinil increased dopamine release. In rodents, Pitolisant was without any effect on locomotion and reduced the cocaine-induced hyperlocomotion. In addition, no locomotor sensitization and no conditioned hyperlocomotion were evidenced with this compound in rats whereas significant effects were elicited by Modafinil. Finally, Pitolisant was devoid of any significant effects in the three standard drug abuse tests (including self-administration in monkeys) and in the physical dependence model. Conclusions and Implications No potential drug abuse liability for Pitolisant was evidenced in various in vivo rodent and primate models, whereas the same does not seem so clear in the case of Modafinil.
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- 2013
5. The histamine H3 receptor: from discovery to clinical trials with pitolisant
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J C Schwartz
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Pharmacology ,Agonist ,Thioperamide ,medicine.medical_specialty ,Pitolisant ,medicine.drug_class ,business.industry ,Histaminergic ,Histamine agonist ,chemistry.chemical_compound ,Histamine receptor ,Endocrinology ,chemistry ,Internal medicine ,medicine ,Inverse agonist ,Histamine H3 receptor ,business ,medicine.drug - Abstract
The third histamine receptor was discovered in 1983 by a traditional pharmacological approach, consisting of assessing the inhibitory effect of histamine on its own release from depolarized rat brain slices. The same in vitro test was used to design, in 1987, the first highly selective and potent H3-autoreceptor ligands, the antagonist thioperamide and the agonist (R)alphamethylhistamine which enhances and inhibits, respectively, the activity of histaminergic neurons in brain. The use of these research tools was instrumental in establishing the main functions of cerebral histaminergic neurons, namely their role in maintenance of wakefulness, attention, learning and other cognitive processes. In 1990, the cloning of the gene of the H3-receptor, a member of the superfamily of heptahelical receptors coupled to G proteins, paved the way to the demonstration of the high constitutive activity of the receptor, including its native form, and its participation in the tonic control of histamine release; it also facilitated the development of H3-receptor inverse agonist programs in many drug companies. Pitolisant (BF2.649, 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride) is the first inverse agonist to be introduced in the clinics. Its wake-promotion activity was evidenced in excessive diurnal sleepiness of patients with narcolepsy, Parkinson's disease or Obstructive Sleep Apnea/Hypopnea, in which this activity is characterized by a mean decrease of the Epworth Sleepiness Scale by about five units. The procognitive activity of this novel class of drugs may also find therapeutic applications in dementias, schizophrenia or attention deficit hyperactivity disorder.
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- 2011
6. Cerebrospinal fluid histamine levels are decreased in patients with narcolepsy and excessive daytime sleepiness of other origin
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Yves Dauvilliers, Michael Croyal, Christian R. Baumann, J C Schwartz, Claudio L. Bassetti, and Philippe Robert
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medicine.medical_specialty ,business.industry ,Cognitive Neuroscience ,Epworth Sleepiness Scale ,Histaminergic ,Excessive daytime sleepiness ,General Medicine ,medicine.disease ,Orexin ,Behavioral Neuroscience ,chemistry.chemical_compound ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Internal medicine ,Medicine ,Wakefulness ,medicine.symptom ,business ,Tuberomammillary nucleus ,Histamine ,Narcolepsy - Abstract
Histaminergic neurons of the hypothalamic tuberomammillary nucleus constitute a major wake-promoting system. In animals, cerebrospinal fluid (CSF) histamine levels are increased during wakefulness and after sleep deprivation and decreased during sleep. An involvement of the histamine system in human disorders has not, to our knowledge, been reported. We measured hypocretin-1 and histamine levels in the lumbar CSF of 28 patients with and without excessive daytime sleepiness (EDS) as assessed by the Epworth Sleepiness Scale (ESS). There were 10 patients with EDS (ESS > 10, mean ESS = 14). Diagnoses included narcolepsy (n = 4), idiopathic hypersomnia (n = 2), sleep apnoea (n = 2) and multiple sclerosis (n = 2). Three patients were treated with stimulants. Their mean CSF histamine was 258 ± 159 PM. There were 18 patients without EDS (ESS < 9, mean ESS = 5). No patients were treated with stimulants. Their mean CSF histamine was significantly higher (624 ± 481 PM, P = 0.007). There was a significant inverse correlation (r = -0.48, P = 0.02) between ESS and both CSF histamine and hypocretin-1 levels. These observations suggest that narcolepsy and EDS of other origin are associated in humans with lower CSF histamine levels and therefore with a reduced activity of the wake-promoting histaminergic neuronal system.
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- 2010
7. Synthesis and evaluation of amides surrogates of dopamine D3 receptor ligands
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Denis Danvy, Mickael Jean, Philippe Robert, J.-C. Schwartz, Thierry Calmels, Marc Capet, Nicolas Levoin, Jacques Renault, Philippe Uriac, Isabelle Berrebi-Bertrand, J.M. Lecomte, Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Laboratoire Bioprojet, Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
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Models, Molecular ,Biodistribution ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Ligands ,01 natural sciences ,Biochemistry ,Chemical synthesis ,Piperazines ,Mice ,chemistry.chemical_compound ,In vivo ,Dopamine receptor D3 ,Amide ,Drug Discovery ,Animals ,Humans ,Moiety ,Selectivity ,Piperazine ,Molecular Biology ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,010405 organic chemistry ,Chemistry ,Ligand ,Organic Chemistry ,Receptors, Dopamine D3 ,Brain ,Amides ,Amide isoster ,Rats ,0104 chemical sciences ,3. Good health ,Bioavailability ,010404 medicinal & biomolecular chemistry ,Dopamine D3 receptor ligand ,Molecular Medicine - Abstract
International audience; Isosteric replacement of the amide function and modulation of the arylpiperazine moiety of known dopamine D3 receptor ligands led to potent and selective compounds. Enhanced bioavailability and preferential brain distribution make compound 6c a good candidate for pharmacological and clinical evaluation.
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- 2010
8. BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, Hydrochloride], a Nonimidazole Inverse Agonist/Antagonist at the Human Histamine H3 Receptor: Preclinical Pharmacology
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F. d'Aniello, Christelle Anaclet, Thierry Calmels, Jeanne-Marie Lecomte, J C Schwartz, Jian-Sheng Lin, Charon Robin Ganellin, J.M. Arrang, Perrin David, Florence Gbahou, Régis Parmentier, Xavier Ligneau, Walter Schunack, J.-C. Camelin, Laurent Landais, C. Drieu la Rochelle, Holger Stark, Valerie Bertaina-Anglade, A. Rouleau, and Isabelle Berrebi-Bertrand
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Male ,Intrinsic activity ,Pitolisant ,Dopamine ,Guinea Pigs ,Scopolamine ,Histamine Antagonists ,Prefrontal Cortex ,Pharmacology ,Histamine Release ,Histamine Agonists ,Mice ,chemistry.chemical_compound ,Piperidines ,Ciproxifan ,medicine ,Animals ,Humans ,Receptors, Histamine H3 ,Inverse agonist ,Methylhistamines ,Imidazoles ,Antagonist ,Histaminergic ,Electroencephalography ,Acetylcholine ,Mice, Inbred C57BL ,chemistry ,Competitive antagonist ,Cats ,Molecular Medicine ,Histamine H3 receptor ,medicine.drug - Abstract
Histamine H3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H3 receptor. On the stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a Ki value of 0.16 nM and as an inverse agonist with an EC50 value of 1.5 nM and an intrinsic activity approximately 50% higher than that of ciproxifan. Its in vitro potency was approximately 6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.
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- 2006
9. Fasidotril: The First Dual Inhibitor of Neprilysin and ACE
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J Bralet, Christine Marie, Claude Gros, J.-C. Schwartz, and J. M. Lecomte
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Pharmacology ,medicine.medical_specialty ,biology ,Chemistry ,fungi ,Dual inhibitor ,Captopril ,Angiotensin-converting enzyme ,medicine.disease ,Endocrinology ,Mechanism of action ,Enzyme inhibitor ,Internal medicine ,Heart failure ,ACE inhibitor ,medicine ,biology.protein ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,human activities ,Neprilysin ,medicine.drug - Abstract
Keywords: Angiotensin converting enzyme; Dual inhibitor; Heart failure; Hypertension; Neprilysin
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- 2006
10. Protean agonism at histamine H 3 receptors in vitro and in vivo
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J C Schwartz, Holger Stark, J. Tardivel-Lacombe, Sylvain Crochet, C. Robin Ganellin, Régis Parmentier, Florence Gbahou, Jian-Sheng Lin, Schunack Walter G, A. Rouleau, Xavier Ligneau, Jean-Michel Arrang, and S. Morisset
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Agonist ,Multidisciplinary ,medicine.drug_class ,Allosteric regulation ,Histamine Antagonists ,Imidazoles ,CHO Cells ,In Vitro Techniques ,Biological Sciences ,Pharmacology ,Biology ,Ligand (biochemistry) ,chemistry.chemical_compound ,chemistry ,Proxyfan ,Cricetinae ,medicine ,Animals ,Receptors, Histamine H3 ,Inverse agonist ,Mitogen-Activated Protein Kinases ,Histamine H3 receptor ,Receptor ,G protein-coupled receptor - Abstract
G protein-coupled receptors (GPCRs) are allosteric proteins that adopt inactive (R) and active (R * ) conformations in equilibrium. R * is promoted by agonists or occurs spontaneously, leading to constitutive activity of the receptor. Conversely, inverse agonists promote R and decrease constitutive activity. The existence of another pharmacological entity, referred to as “protean” agonists (after Proteus, the Greek god who could change shape), was assumed on theoretical grounds. It was predicted from the existence of constitutive activity that a same ligand of this class could act either as an agonist or an inverse agonist at the same GPCR. Here, we show that proxyfan, a high-affinity histamine H 3 -receptor ligand, acts as a protean agonist at recombinant H 3 receptors expressed in the same Chinese hamster ovary cells. In support of the physiological relevance of the process, we show that proxyfan also behaves as a protean agonist at native H 3 receptors known to display constitutive activity. On neurochemical and behavioral responses in rodents and cats, proxyfan displays a spectrum of activity ranging from full agonism to full inverse agonism. Thus, protean agonism demonstrates the existence of ligand-directed active states LR * different from, and competing with, constitutively active states R * of GPCRs, and defines a pharmacological entity with important therapeutic implications.
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- 2003
11. Constitutive activity of the recombinant and native histamine H3 receptor
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J.-C. Schwartz, A. Rouleau, Holger Stark, Walter Schunack, Charon Robin Ganellin, J. Tardivel-Lacombe, J.M. Arrang, Florence Gbahou, X. Ligneau, and S. Morisset
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Thioperamide ,General Medicine ,Histamine H1 receptor ,Biology ,Pharmacology ,chemistry.chemical_compound ,Histamine receptor ,chemistry ,Histamine H2 receptor ,Proxyfan ,Ciproxifan ,medicine ,Inverse agonist ,Histamine H3 receptor ,medicine.drug - Abstract
Although constitutive activity was shown to occur with many recombinant and/or mutated G-protein-coupled receptors, the physiological relevance of the process has remained debated. We have further explored this important issue with the histamine H3 receptor (H3R), a presynaptic receptor regulating histamine neuron activity in the brain. Constitutive activity of the recombinant receptor was studied using [3H]arachidonic acid release, [35S]GTPγ[S] binding and inhibition of cAMP accumulation. Evidence for constructive activity was obtained in these three functional assays with two isoforms of the rat H3 receptor, as well as with the human H3 receptor, expressed at physiological densities. Several standard H3-receptor antagonists, such as thioperamide and ciproxifan, were in fact acting as potent inverse agonists. Proxyfan opposed both agonists and inverse agonists and was therefore identified as a neutral antagonist. Using these drugs, we show high constitutive activity of native receptors. [35S]GTPγ[S] binding demonstrated constitutive activity of H3 receptors expressed at a normal level in mouse or rat brain. Constitutive activity of presynaptic H3 autoreceptors modulates histamine release from cortical synaptosomes in vitro and controls histamine neuron activity in vivo. This implies that inverse agonists rather than neutral antagonists may find therapeutic applications.
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- 2003
12. Guinea Pig Histamine H1 Receptor. I. Gene Cloning, Characterization, and Tissue Expression Revealed by In Situ Hybridization
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J.M. Arrang, J.-C. Schwartz, Jean-Jacques Diaz, Elisabeth Traiffort, R. Leurs, J. Tardivel-Lacombe, and Martial Ruat
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Male ,Guinea Pigs ,Molecular Sequence Data ,CHO Cells ,In situ hybridization ,Biology ,Transfection ,Biochemistry ,Cellular and Molecular Neuroscience ,Cricetinae ,Gene expression ,Animals ,5-HT5A receptor ,Amino Acid Sequence ,RNA, Messenger ,Receptors, Histamine H1 ,Northern blot ,Cloning, Molecular ,Rats, Wistar ,Receptor ,In Situ Hybridization ,Southern blot ,Pyrilamine ,Binding Sites ,Base Sequence ,Chinese hamster ovary cell ,Brain ,Blotting, Northern ,Molecular biology ,Rats ,Blot ,Blotting, Southern ,Oligonucleotide Probes - Abstract
An intronless DNA encoding the guinea pig H1 receptor was cloned from a genomic library using probes derived from the bovine H1 receptor. It encodes a protein of 488 amino acids with a calculated molecular mass of 55,619 daltons compared with a size of 56-68 kDa for the photoaffinity-labeled receptor as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. The protein displays a 66% homology with the bovine receptor. Stable expression of the H1 receptor, characterized by the appearance of [3H]mepyramine binding sites with a pharmacology similar to that of the native H1 receptor, was obtained following transfection of Chinese hamster ovary cells. Southern blot analysis, using a variety of restriction enzymes, did not provide any evidence of multiple H1 isoreceptors. Northern blot analysis of a variety of guinea pig peripheral or cerebral tissues identified, in most cases, a single transcript of 3.3 kb, but also, in some tissues, a second transcript of 3.7 kb, possibly generated by the use of different promoter or polyadenylation sites or corresponding to a transcript from a distinct gene. In situ hybridization studies showed the highly contrasted cerebral expression of H1-receptor gene transcripts, which was compared with autoradiographic receptor localization. This allowed the identification of some major cell populations expressing the H1 receptor, e.g., Purkinje cells in cerebellum or pyramidal cells in the hippocampal complex.
- Published
- 2002
13. Neurochemical Evidence that Postsynaptic Nucleus Accumbens D3 Receptor Stimulation Enhances Cocaine Reinforcement
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S B Caine, Pierre Sokoloff, J.-C. Schwartz, Friedbert Weiss, George F. Koob, and Loren H. Parsons
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Male ,Agonist ,medicine.medical_specialty ,Pyrrolidines ,Tetrahydronaphthalenes ,Quinelorane ,medicine.drug_class ,Dopamine ,Microdialysis ,Self Administration ,Striatum ,Naphthalenes ,Nucleus accumbens ,Biochemistry ,Nucleus Accumbens ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Cocaine ,Dopamine receptor D3 ,Internal medicine ,Basal ganglia ,medicine ,Animals ,Rats, Wistar ,Receptors, Dopamine D2 ,Receptors, Dopamine D3 ,Nafadotride ,Rats ,Neostriatum ,Dopamine D2 Receptor Antagonists ,Endocrinology ,chemistry ,Dopamine Agonists ,Quinolines ,Dopamine Antagonists ,medicine.drug - Abstract
The mechanism by which two D3 receptor-preferring agonists, 7-hydroxydipropylaminotetralin (7-OH-DPAT) and quinelorane, modulate cocaine reinforcement was examined by monitoring nucleus accumbens dopamine levels with in vivo microdialysis while rats intravenously self-administered the following four different drug solutions consecutively: (1) cocaine; (2) a combination of cocaine plus a low dose of either agonist; (3) either agonist alone; and finally, (4) a physiological saline solution. Both 7-OH-DPAT (4 micrograms/infusion) and quinelorane (0.25 microgram/infusion) decreased cocaine (0.25 mg/infusion) intake in a manner indicating an enhancement of cocaine reinforcement and simultaneously decreased the cocaine-induced elevations in nucleus accumbens dopamine levels by > 50%. Subsequent self-administration of either 7-OH-DPAT (4 micrograms/infusion) or quinelorane (0.25 microgram/infusion) alone resulted in significant, but stable, increases in drug intake, with a concurrent decrease in nucleus accumbens dopamine levels to approximately 50% below nondrug baseline levels. These findings indicate that postsynaptic D3 receptor stimulation in the nucleus accumbens enhances the reinforcing properties of cocaine. In a second experiment, local application of 7-OH-DPAT via reverse dialysis (30 and 100 nM perfusate concentrations) dose-dependently decreased nucleus accumbens dopamine efflux to 76 +/- 3.9 and 61 +/- 6.3% of baseline, respectively, whereas there was no effect of this agonist on dopamine efflux in the ipsilateral striatum of these same animals. Coperfusion with the D3 receptor-preferring antagonist nafadotride dose-dependently blocked the effect of 7-OH-DPAT on nucleus accumbens dopamine efflux. These results suggest that, at low concentrations, 7-OH-DPAT selectively activates D3 receptors in vivo.
- Published
- 2002
14. Co-localization of histamine with GABA but not with galanin in the human tuberomamillary nucleus
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B. Fisser, C. Chotard, Suzanne Trottier, Dick F. Swaab, J.-C. Schwartz, Unga A. Unmehopa, Elisabeth Traiffort, Netherlands Institute for Neuroscience (NIN), Outters-Lafaye, Michèle, Unité de Neurobiologie et Pharmacologie Moléculaire, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Netherlands Institute for Brain Research, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Other departments
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Male ,MESH : RNA, Messenger ,MESH : Immunohistochemistry ,MESH : Aged ,MESH: gamma-Aminobutyric Acid ,Histidine Decarboxylase ,chemistry.chemical_compound ,MESH: Aged, 80 and over ,MESH : Female ,MESH : Autopsy ,In Situ Hybridization ,gamma-Aminobutyric Acid ,MESH: Aged ,Aged, 80 and over ,MESH : Isoenzymes ,MESH: Middle Aged ,Glutamate Decarboxylase ,General Neuroscience ,Glutamate receptor ,MESH : In Situ Hybridization ,MESH : Hypothalamic Area, Lateral ,MESH: Hypothalamic Area, Lateral ,Middle Aged ,MESH : Adult ,MESH : Galanin ,Immunohistochemistry ,MESH : gamma-Aminobutyric Acid ,Isoenzymes ,MESH : Histamine ,medicine.anatomical_structure ,Hypothalamus ,MESH: Isoenzymes ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Female ,Autopsy ,MESH: Histamine ,Tuberomammillary nucleus ,Histamine ,MESH: Glutamate Decarboxylase ,Adult ,medicine.medical_specialty ,MESH : Histidine Decarboxylase ,MESH : Male ,Galanin ,In situ hybridization ,Biology ,MESH: In Situ Hybridization ,MESH: Galanin ,Internal medicine ,medicine ,Humans ,MESH : Middle Aged ,RNA, Messenger ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,MESH : Aged, 80 and over ,Molecular Biology ,MESH: RNA, Messenger ,Aged ,MESH : Glutamate Decarboxylase ,MESH: Humans ,MESH : Humans ,Histaminergic ,MESH: Adult ,MESH: Immunohistochemistry ,MESH: Male ,Endocrinology ,nervous system ,chemistry ,Hypothalamic Area, Lateral ,Neurology (clinical) ,MESH: Autopsy ,MESH: Female ,MESH: Histidine Decarboxylase ,Nucleus ,Developmental Biology - Abstract
International audience; The presence of GABA and galanin in histaminergic neurons was previously reported in the rodent brain but whether such co-localizations also occur in the human brain was not known. We used in situ hybridization histochemistry and immunohistochemistry to study the co-localization of histamine with GABA and galanin in neurons of the tuberomamillary nucleus of adult human posterior hypothalamus. On consecutive formalin-fixed paraffin-embedded sections, co-localization was assessed using the in situ hybridization for L-histidine decarboxylase mRNA and immunocytochemistry for glutamate decarboxylase-67 kDa or galanin in the two profiles of same cell. The pattern of distribution and number of histaminergic neurons identified by in situ hybridization of the synthesizing enzyme gene transcripts were in accordance with data reported for histamine immunoreactivity. The great majority of neurons within the main divisions of the tuberomamillary nucleus containing L-histidine decarboxylase mRNA was also immunoreactive for glutamate decarboxylase-67 kDa. The range of co-localization of the two markers varied from 72% in the lateral part, to 75-87% in the medial part and 83-88% in the ventral part. In contrast, no cell containing L-histidine decarboxylase mRNA was immunoreactive for galanin. We conclude that tuberomamillary neurons in human co-express histamine with GABA but, unlike the neurons in rodents, do not express galanin, indicating that neurotransmitter co-localization patterns differ in the two species.
- Published
- 2002
15. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial
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J C Schwartz, Gert Jan Lammers, Isabelle Arnulf, Geert Mayer, Yves Dauvilliers, Claudio L. Bassetti, Philippe Lehert, Jeanne-Marie Lecomte, Andrea Rodenbeck, and Claire-Li Ding
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Adult ,Male ,Cataplexy ,Pitolisant ,Population ,Excessive daytime sleepiness ,Modafinil ,Placebo ,Severity of Illness Index ,law.invention ,Histamine Agonists ,Placebos ,chemistry.chemical_compound ,Young Adult ,Randomized controlled trial ,Double-Blind Method ,Piperidines ,law ,medicine ,Humans ,Benzhydryl Compounds ,education ,Narcolepsy ,education.field_of_study ,business.industry ,Epworth Sleepiness Scale ,Wakefulness-Promoting Agents ,Middle Aged ,Treatment Outcome ,chemistry ,Anesthesia ,Female ,Neurology (clinical) ,medicine.symptom ,business ,medicine.drug - Abstract
Summary Background Narcolepsy is characterised by excessive daytime sleepiness (EDS) and cataplexy. Histamine neurons are crucial to maintain wakefulness. We assessed the safety and efficacy of pitolisant (previously called BF2.649), a selective histamine H3 receptor inverse agonist that activates these neurons, in patients with narcolepsy. Methods For this double-blind, randomised, parallel-group controlled trial, we recruited patients with narcolepsy from 32 sleep disorder centres in five European countries. Patients were eligible if they were aged 18 years or older, had not taken psychostimulants for at least 14 days, and had EDS (defined as an Epworth Sleepiness Scale [ESS] score of at least 14). Using a computer-generated randomisation sequence, we randomly allocated patients to receive pitolisant, modafinil, or placebo (1:1:1). Treatment lasted 8 weeks: 3 weeks of flexible dosing according to investigator's judgment (10 mg, 20 mg, or 40 mg a day of pitolisant; 100 mg, 200 mg or 400 mg a day of modafinil) followed by 5 weeks of stable dosing. Patients took four tablets a day in a double-dummy design to ensure masking. For the primary analysis, assessed in the intention-to-treat population, we assessed the superiority of pitolisant versus placebo, and the non-inferiority of pitolisant versus modafinil. This trial is registered with ClinicalTrials.gov, number NCT01067222. Findings Between May 26, 2009, and June 30, 2010, we screened 110 patients, 95 of whom were eligible and randomly assigned to treatment: 30 to placebo, 32 to pitolisant, and 33 to modafinil. Over the 8-week treatment period, mean ESS score reductions were −3·4 (SD 4·2) in the placebo group, −5·8 (6·2) in the pitolisant group, and −6·9 (6·2) in the modafinil group. Our primary analysis of between-group differences in mean ESS score at endpoint (adjusted for baseline) showed pitolisant to be superior to placebo (difference −3·0, 95% CI −5·6 to −0·4; p=0·024), but not non-inferior to modafinil (difference 0·12, 95% CI −2·5 to 2·7; p=0·250). We recorded 22 adverse events with pitolisant, 26 with modafinil, and ten with placebo. Six severe adverse events were treatment-related: one with pitolisant (abdominal discomfort) and five with modafinil (abdominal pain, abnormal behaviour, amphetamine-like withdrawal symptoms, lymphoadenopathy, and inner ear disorders). Interpretation Pitolisant at doses up to 40 mg was efficacious on EDS compared with placebo and well tolerated compared with modafinil. If these findings are substantiated in further studies, pitolisant could offer a new treatment option for patients with narcolepsy. Funding Bioprojet, France.
- Published
- 2013
16. Distinct pharmacology of rat and human histamine H3receptors: role of two amino acids in the third transmembrane domain
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Xavier Ligneau, J. Tardivel-Lacombe, J.M. Arrang, Florence Gbahou, Holger Stark, Walter Schunack, S. Morisset, J.-C. Schwartz, and Charon Robin Ganellin
- Subjects
Pharmacology ,chemistry.chemical_classification ,Clobenpropit ,Biology ,Molecular biology ,Amino acid ,chemistry.chemical_compound ,Histamine receptor ,Transmembrane domain ,Biochemistry ,chemistry ,Proxyfan ,Ciproxifan ,medicine ,Histamine H3 receptor ,Peptide sequence ,medicine.drug - Abstract
Starting from the sequence of the human histamine H3 receptor (hH3R) cDNA, we have cloned the corresponding rat cDNA. Whereas the two deduced proteins show 93.5% overall homology and differ only by five amino acid residues at the level of the transmembrane domains (TMs), some ligands displayed distinct affinities. Thioperamide and ciproxifan were about 10 fold more potent at the rat than at the human receptor, whereas FUB 349 displayed a reverse preference. Histamine, (R)α-methylhistamine, proxyfan or clobenpropit were nearly equipotent at H3 receptors of both species. The inverse discrimination patterns of ciproxifan and FUB 349 were partially changed by mutation of one amino acid (V122A), and fully abolished by mutation of two amino acids (A119T and V122A), in TM3 of the rH3R located in the vicinity of Asp114 purported to salt-link the ammonium group of histamine. Therefore, these two residues appear to be responsible for the distinct pharmacology of the H3R in the two species.
- Published
- 2000
17. Analogues and derivatives of ciproxifan, a novel prototype for generating potent histamine H3-receptor antagonists
- Author
-
Jean-Michel Arrang, Xavier Ligneau, J.‐C. Schwartz, Bassem Sadek, Schunack Walter G, Holger Stark, and C. Robin Ganellin
- Subjects
Stereochemistry ,Clinical Biochemistry ,Histamine Antagonists ,Pharmaceutical Science ,Histamine Release ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Ciproxifan ,Drug Discovery ,medicine ,Animals ,Receptors, Histamine H3 ,Moiety ,Molecular Biology ,Cerebral Cortex ,Molecular Structure ,Chemistry ,Organic Chemistry ,Imidazoles ,Antagonist ,In vitro ,Rats ,Drug Design ,Molecular Medicine ,Histamine H3 receptor ,Histamine ,Synaptosomes ,medicine.drug - Abstract
Novel derivatives of the highly potent and selective histamine H-3-receptor antagonist ciproxifan (3) with different chain lengths as well as with structural variants of the cyclopropyl ketone moiety have been prepared and screened for their antagonist H3-receptor potencies in vitro and in vivo. Some derivatives (2, 6-8, 12) containing other functionalities were effective in vitro in the same (sub)nanomolar concentration range and in vivo in a remarkably low oral dose. (C) 2000 Elsevier Science Ltd. All rights reserved
- Published
- 2000
18. Novel Histamine H3-Receptor Antagonists with Carbonyl-Substituted 4-(3-(Phenoxy)propyl)-1H-imidazole Structures like Ciproxifan and Related Compounds
- Author
-
J.-C. Schwartz, Holger Stark, Charon Robin Ganellin, B Sadek, A Huls, Walter Schunack, X Ligneau, Michael Krause, and J.M. Arrang
- Subjects
Ketone ,Stereochemistry ,Guinea Pigs ,Drug Evaluation, Preclinical ,Histamine Antagonists ,In Vitro Techniques ,Histamine Release ,Chemical synthesis ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Histamine receptor ,Ileum ,In vivo ,Ciproxifan ,Drug Discovery ,medicine ,Animals ,Receptors, Histamine H3 ,Imidazole ,Receptors, Histamine H2 ,Heart Atria ,Receptors, Histamine H1 ,Cerebral Cortex ,chemistry.chemical_classification ,Imidazoles ,Antagonist ,Muscle, Smooth ,Haplorhini ,Atrial Function ,Rats ,chemistry ,Molecular Medicine ,Histamine ,Muscle Contraction ,Synaptosomes ,medicine.drug - Abstract
Novel histamine H(3)-receptor antagonists possessing a 4-(3-(phenoxy)propyl)-1H-imidazole structure generally substituted in the para-position of the phenyl ring have been synthesized according to Mitsunobu or S(N)Ar reactions. With in vitro and in vivo screening for H(3)-receptor antagonist potency, the carbonyl-substituted derivatives proved to be highly active compounds. A number of compounds showed in vitro affinities in the subnanomolar concentration range, and the 4-hexanoyl (10) and 4-acetyl-3-methyl (29) substituted derivatives showed in vivo antagonist potencies of about 0.1 mg/kg after po administration. Many proxifans were also tested for their affinities at other histamine receptor subtypes thereby demonstrating their pronounced H(3)-receptor subtype selectivity. Since the cyclopropyl ketone derivative 14 (ciproxifan) had high affinity in vitro as well as high potency in vivo, it was selected for further studies in monkeys. It showed good oral absorption and long-lasting, dose-dependent plasma levels making it a promising compound for drug development.
- Published
- 2000
19. Selective increase of dopamine D3 receptor gene expression as a common effect of chronic antidepressant treatments
- Author
-
C.H. Lammers, Diaz J, J.-C. Schwartz, and Pierre Sokoloff
- Subjects
Male ,Imipramine ,medicine.medical_specialty ,Monoamine Oxidase Inhibitors ,Amitriptyline ,Dopamine ,Gene Expression ,Antidepressive Agents, Tricyclic ,Substance P ,Nucleus accumbens ,Dynorphins ,Nucleus Accumbens ,Cellular and Molecular Neuroscience ,Dopamine receptor D1 ,Dopamine receptor D3 ,Fluoxetine ,Internal medicine ,Desipramine ,Dopamine receptor D2 ,Limbic System ,medicine ,Animals ,RNA, Messenger ,Rats, Wistar ,Molecular Biology ,Electroshock ,Receptors, Dopamine D2 ,Dopaminergic ,Receptors, Dopamine D3 ,Rats ,Psychiatry and Mental health ,Endocrinology ,Antidepressive Agents, Second-Generation ,Tranylcypromine ,Islands of Calleja ,Psychology ,medicine.drug - Abstract
The mesolimbic dopaminergic system is a neuroanatomical key structure for reward and motivation upon which previous studies indicated that antidepressant drugs exert a stimulatory influence, via still unknown neurobiological mechanisms. Here we examined the effects of chronic administration of antidepressants of several classes (amitriptyline, desipramine, imipramine, fluoxetine and tranylcypromine) and repeated electroconvulsive shock treatments (ECT) on dopamine D3 receptor expression in the shell of the nucleus accumbens, a major projection area of the mesolimbic dopaminergic system. Short-term drug treatments had variable effects on D3 receptor mRNA expression. In contrast, treatments for 21 days (with all drugs except fluoxetine) significantly increased D3 receptor mRNA expression in the shell of nucleus accumbens; D3 receptor binding was also significantly increased by amitriptyline or fluoxetine after a 42-day treatment. ECT for 10 days increased D3 receptor mRNA and binding in the shell of nucleus accumbens. D1 receptor and D2 receptor mRNAs were increased by imipramine and amitriptyline, but not by the other treatments. The time-course of altered D3 receptor expression, in line with the delayed clinical efficiency of antidepressant treatment, and the fact that various antidepressant drugs and ECT treatments eventually produced the same effects, suggest that increased expression of the D3 receptor in the shell of nucleus accumbens is a common neurobiological mechanism of antidepressant treatments, resulting in enhanced responsiveness to the mesolimbic dopaminergic system.
- Published
- 2000
20. Immunolocalization of tripeptidyl peptidase II, a cholecystokinin-inactivating enzyme, in rat brain
- Author
-
Ph Rostaing, J.-C. Schwartz, Antoine Triller, Christiane Rose, and Patricia Facchinetti
- Subjects
Male ,medicine.medical_specialty ,Cerebellum ,Neuropeptide ,Biology ,Aminopeptidases ,Tripeptidyl peptidase ,Internal medicine ,medicine ,Animals ,Tissue Distribution ,Rats, Wistar ,Dipeptidyl-Peptidases and Tripeptidyl-Peptidases ,Cholecystokinin ,General Neuroscience ,Serine Endopeptidases ,digestive, oral, and skin physiology ,Brain ,Tripeptidyl peptidase II ,Immunohistochemistry ,Rats ,Cell biology ,Microscopy, Electron ,medicine.anatomical_structure ,Endocrinology ,nervous system ,Cerebral cortex ,Median eminence ,Pyramidal cell ,hormones, hormone substitutes, and hormone antagonists - Abstract
Tripeptidyl peptidase II (EC 3.4.14.10) is a serine peptidase apparently involved in the inactivation of cholecystokinin octapeptide [Rose C. et al . (1996) Nature 380 , 403–409]. We have compared its distribution with that of cholecystokinin in rat brain, using a polyclonal antibody raised against a highly purified preparation for immunohistochemistry at the photon and electron microscope levels. Tripeptidyl peptidase II-like immunoreactivity was mostly detected in neurons, and also in ependymal cells and choroid plexuses, localizations consistent with a possible participation of the peptidase in the inactivation of cholecystokinin circulating in the cerebrospinal fluid. Immunoreactivity was mostly detected in cell bodies, large processes and, to a lesser extent, axons of various neuronal populations. Their localizations, relative to that of cholecystokinin terminals, appears to define three distinct situations. The first corresponds to neurons with high immunoreactivity in areas containing cholecystokinin terminals, as in the cerebral cortex or hippocampal formation, where pyramidal cell bodies and processes surrounded by cholecystokinin axons were immunoreactive. A similar situation was encountered in many other areas, namely along the pathways through which cholecystokinin controls satiety, i.e. in sensory vagal neurons, the nucleus tractus solitarius and hypothalamic nuclei. The second situation corresponds to cholecystokinin neuronal populations containing tripeptidyl peptidase II-like immunoreactivity, as in neurons of the supraoptic or paraventricular nuclei, axons in the median eminence or nigral neurons. In both these situations, localization of tripeptidyl peptidase II-like immunoreactivity is consistent with a role in cholecystokinin inactivation. The third situation corresponds to areas with mismatches, such as the cerebellum, a region devoid of cholecystokinin, but in which Purkinje cells displayed high tripeptidyl peptidase II-like immunoreactivity, possibly related to a role in the inactivation of neuropeptides other than cholecystokinin. Also, some areas with cholecystokinin terminals, e.g., the molecular layer of the cerebral cortex, were devoid of tripeptidyl peptidase II-like immunoreactivity, suggesting that processes other than cleavage by tripeptidyl peptidase II may be involved in cholecystokinin inactivation. Tripeptidyl peptidase II-like immunoreactivity was also detected at the ultrastructural level in the cerebral cortex and hypothalamus using either immunoperoxidase or silver-enhanced immunogold detection. It was mainly associated with the cytoplasm of neuronal somata and dendrites, often in the vicinity of reticulum cisternae, Golgi apparatus or vesicles, and with the inner side of the dendritic plasma membrane. Hence, whereas a fraction of tripeptidyl peptidase II-like immunoreactivity localization at the cellular level is consistent with its alleged function in cholecystokinin octapeptide inactivation, its association with the outside plasma membrane of neurons remains to be confirmed.
- Published
- 1999
21. Synthesis of Potent Non-imidazole Histamine H3-Receptor Antagonists
- Author
-
A Piripitsi, J.M. Arrang, X Ligneau, Walter Schunack, Fabien Leurquin, J.-C. Schwartz, Charon Robin Ganellin, and Monique Garbarg
- Subjects
chemistry.chemical_compound ,chemistry ,Tertiary amine ,Stereochemistry ,Drug Discovery ,Antagonist ,Pharmaceutical Science ,Imidazole ,Amine gas treating ,Histamine H3 receptor ,Chemical synthesis ,Pyrrolidine ,Histamine - Abstract
Histamine has been converted into a non-imidazole H3-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N alpha-position followed by removal of the imidazole ring. The resulting compound, N-ethyl-N-(4-phenylbutyl)amine, remarkably has a Ki = 1.3 microM as an H3 antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure-activity studies furnished N-(5-phenoxypentyl)pyrrolidine (Ki = 0.18 +/- 0.10 microM, for [3H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO2 into the para position of the phenoxy group gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (Ki = 39 +/- 11 nM), ED50 = 1.1 +/- 0.6 mg/kg per os in mice on brain tele-methylhistamine levels.
- Published
- 1998
22. 4-Alkynylphenyl Imidazolylpropyl Ethers as Selective Histamine H3-Receptor Antagonists with High Oral Central Nervous System Activity
- Author
-
Walter Schunack, Holger Stark, M. Garbarg, X. Ligneau, J.‐C. Schwartz, and M. Krause
- Subjects
Guinea Pigs ,Central nervous system ,Histamine Antagonists ,Administration, Oral ,Ether ,In Vitro Techniques ,Histamine Release ,Mice ,chemistry.chemical_compound ,Ileum ,In vivo ,Oral administration ,Drug Discovery ,medicine ,Animals ,Receptors, Histamine H3 ,Receptors, Histamine H2 ,Receptors, Histamine H1 ,Cerebral Cortex ,Chemistry ,Myocardium ,Imidazoles ,Antagonist ,In vitro ,Rats ,HYDIA ,medicine.anatomical_structure ,Biochemistry ,Molecular Medicine ,Histamine H3 receptor ,Ethers ,Synaptosomes - Abstract
In search for potent and therapeutically useful H3-receptor antagonists, we prepared novel 4-alkynylphenyl ether derivatives of 3-(1H-imidazol-4-yl)propanol in a convenient synthetic route. All compounds were tested for in vitro and in vivo H3-receptor antagonist activity as well as for H3-receptor selectivity versus H1- and H2-receptors. The presented 4-alkynylphenyl ethers are highly potent and selective H3 antagonists showing oral activity and improved brain penetration. Particularly 4-ethynylphenyl 3-(1H-imidazol-4-yl)propyl ether (14a) displays striking in vitro and in vivo activity with a -log Ki value of 8.6 and an ED50 value of 0.12 mg/kg. At present 14a is the most potent H3-receptor antagonist in vivo and may therefore be a potential drug for the therapy of H3-receptor-dependent diseases of the central nervous system (CNS).
- Published
- 1998
23. Homozygosity at the dopamine D3 receptor gene is associated with opiate dependence
- Author
-
E Duaux, Pierre Sokoloff, J.-C. Schwartz, F. Sautel, Henri Lôo, M.-F. Poirier, Nathalie Griffon, Marie-Chantal Bourdel, P. Gorwood, and Jean Adès
- Subjects
Adult ,Male ,medicine.medical_specialty ,Genotype ,media_common.quotation_subject ,Polymerase Chain Reaction ,Genetic determinism ,Cellular and Molecular Neuroscience ,Reference Values ,Polymorphism (computer science) ,Dopamine receptor D3 ,Internal medicine ,medicine ,Humans ,Allele ,Deoxyribonucleases, Type II Site-Specific ,Molecular Biology ,media_common ,Receptors, Dopamine D2 ,Addiction ,Homozygote ,Receptors, Dopamine D3 ,Opioid-Related Disorders ,medicine.disease ,Substance abuse ,Psychiatry and Mental health ,Endocrinology ,France ,Morbidity ,Opiate ,Psychology ,Polymorphism, Restriction Fragment Length ,Personality - Abstract
Anatomical, pharmacological and human post-mortem studies suggest the dopamine D3 receptor (DRD3) gene as a candidate for drug dependence. We thus performed an association study of the Bal I polymorphism at the DRD3 gene, including 54 opiate addicts and 70 controls. Opiate addicts had a higher sensation-seeking score (on the Zückerman scale) than controls (P = 0.001), particularly a subgroup (70%) who had a distinctly higher score, exceeding 24. There were no marked differences in genotypes between patients as a whole and controls. However, patients with a sensation-seeking score above 24 were more frequently homozygotes for both alleles than patients with a sensation-seeking score under 24 (P = 0.038) or controls (P = 0.034). Although obtained in a sample of limited size, these results suggest that the DRD3 gene may have a role in drug dependence susceptibility in individuals with high sensation-seeking scores. This hypothesis is consistent with the role of DRD3 in mediating responses to drugs of abuse in animals and the association of homozygosity at the Bal I polymorphism with drug abuse in schizophrenic patients (see companion article by Krebs et al).
- Published
- 1998
24. A rat G protein-coupled receptor selectively expressed in myelin-forming cells
- Author
-
Bernard Zalc, S. Barrón, J. ‐C. Schwartz, C. Lubetzki, P. Sokoloff, Julien Allard, and J. Diaz
- Subjects
Orphan receptor ,Nervous system ,Glial fibrillary acidic protein ,General Neuroscience ,Schwann cell ,Biology ,Oligodendrocyte ,Cell biology ,Neuroepithelial cell ,Myelin ,medicine.anatomical_structure ,nervous system ,Myelin maintenance ,medicine ,biology.protein ,Neuroscience - Abstract
By screening an olfactory bulb cDNA library using dopamine receptor probes, we isolated the cDNA coding for the rat counterpart of an orphan receptor known as Edg-2, homologous to G protein-coupled receptors. In situ hybridization analysis showed that Edg-2 mRNA expression is restricted to myelinated structures, e.g. corpus callosum or peripheral nerves. A weaker expression in various peripheral organs was also detected in newborns. A 3.8-kb transcript was found at high levels in highly myelinated brain structures and sciatic nerve, and, at lower levels, in poorly myelinated peripheral organs, consistent with its occurrence in Schwann cells in the peripheral nervous system. One hundred percent of Edg-2 mRNA-containing cells in the brain also expressed mRNA encoding myelin-basic-protein, a marker of oligodendrocytes. This restricted olygodendrocytes localization was confirmed by the absence of cellular colocalization of Edg-2 and glial fibrillary acidic protein, an astrocytic marker. During prenatal development, Edg-2 mRNA expression was high in the cortical neuroepithelium and meningeal layer at E16, extended later to other neuroepithelia, and disappeared shortly after birth. During brain postnatal development, Edg-2 mRNA expression in myelinated structures followed a caudo-rostral gradient, similar to that of myelination. Thus, Edg-2 is the first G protein-coupled receptor found to be selectively expressed in myelin-forming cells in the nervous system and its temporal expression pattern is consistent with a dual role (i) in neurogenesis, during embryonic development, and (ii) in myelination and myelin maintenance, during postnatal life.
- Published
- 1998
25. D3 receptor test in vitro predicts decreased cocaine self-administration in rats
- Author
-
Loren H. Parsons, J C Schwartz, Pierre Sokoloff, George F. Koob, Barry J. Everitt, and S B Caine
- Subjects
Male ,medicine.medical_specialty ,Pyrrolidines ,Quinelorane ,Self Administration ,In Vitro Techniques ,Naphthalenes ,Pharmacology ,chemistry.chemical_compound ,Pramipexole ,Quinpirole ,Cocaine ,Dopamine receptor D3 ,Dopamine ,Internal medicine ,Oxazines ,medicine ,Animals ,Benzopyrans ,Benzothiazoles ,Receptors, Dopamine D2 ,General Neuroscience ,Receptors, Dopamine D3 ,Nafadotride ,Opioid-Related Disorders ,Rats ,Apomorphine ,Thiazoles ,Endocrinology ,BP-897 ,chemistry ,Dopamine Agonists ,Quinolines ,Dopamine Antagonists ,Lisuride ,medicine.drug - Abstract
THE three dopamine agonists with highest reported D 3 receptor selectivity in vitro, pramipexole, quinelorane and PD128,907, decreased self-administration of a high dose of cocaine in rats as a result of a leftward shift in the cocaine dose-effect function. In contrast the D 3 preferring antagonist nafadotride increased cocaine self-administration. Moreover the relative potencies of these and other D 2 -like dopamine agonists (lisuride, 7-OH-DPAT, quinpirole, apomorphine, bromocriptine) to modulate cocaine self-administration were highly correlated with their relative potencies for increasing mitogenesis in vitro in cell lines expressing D 3 but not D 2 receptors. These results support the hypothesis that the D 3 receptor may be an important target for pharmacotherapies for cocaine abuse and dependence.
- Published
- 1997
26. Detailed mapping of the histamine H2 receptor and its gene transcripts in guinea-pig brain
- Author
-
E. Souil, Marisa Vizuete, J.-C. Schwartz, J. Tardivel-Lacombe, Elisabeth Traiffort, M.L. Bouthenet, Martial Ruat, Laboratoire de Physiologie, Faculté de Pharmacie, Université René Descartes, Unité de Neurobiologie et Pharmacologie Moléculaire [Centre Paul Broca] (U109 INSERM ), Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), and PERIGNON, Alain
- Subjects
Male ,Cerebellum ,Transcription, Genetic ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,[SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior ,Hippocampal formation ,MESH: Radioligand Assay ,Guanidines ,Iodine Radioisotopes ,Radioligand Assay ,MESH: Autoradiography ,MESH: Animals ,MESH: Brain Chemistry ,Cloning, Molecular ,Receptor ,MESH: Brain Mapping ,In Situ Hybridization ,Brain Mapping ,[SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior ,Cerebrum ,General Neuroscience ,[SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences ,Brain ,MESH: Iodine Radioisotopes ,MESH: Guanidines ,medicine.anatomical_structure ,Histamine H2 Antagonists ,Cerebral cortex ,Cerebellar cortex ,MESH: Histamine H2 Antagonists ,Guinea Pigs ,MESH: Receptors, Histamine H2 ,Biology ,MESH: Guinea Pigs ,MESH: Brain ,MESH: In Situ Hybridization ,medicine ,Animals ,MESH: Cloning, Molecular ,Receptors, Histamine H2 ,RNA, Messenger ,MESH: RNA, Messenger ,Brain Chemistry ,MESH: Transcription, Genetic ,Dentate gyrus ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Histaminergic ,MESH: Male ,nervous system ,Autoradiography ,Neuroscience ,[SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences - Abstract
International audience; Autoradiographic studies of the distribution of the histamine H2 receptor and its messenger RNAs were performed on serial frontal and a few sagittal sections of guinea-pig brain using [(125)I]iodoaminopotentidine for radioligand binding and a 33P-labelled complementary RNA probe for in situ hybridization, respectively. Both probes were validated by assessing non-specific labelling using non-radioactive competing H2 receptor ligands and a sense probe for binding sites and gene transcripts, respectively. In some areas, e.g., cerebral cortex, hippocampal complex or cerebellum, such studies were completed by identification of neurons expressing the H2 receptor messenger RNAs on emulsion-dipped sections. Nissl-stained sections from comparable levels were used to localize brain structures. In many brain areas, the distribution of the H2 receptor and its messenger RNAs appeared to parallel that known for histaminergic axons. For instance. high levels of both H2 receptor markers were detected in striatal and limbic areas known to receive abundant histaminergic projections. In contrast, in septum, hypothalamic, pontine and several thalamic nuclei, a comparatively low density of both H2 receptor markers was detected, suggesting that histamine actions in these areas are mediated by H1 and/or H3 receptors. Generally, the distribution of H2 receptor messenger RNA correlates well with that of [(125)I]iodoaminopotentidine binding sites, although some differences were observed. In a few regions (e.g., substantia nigra, locus coeruleus) high or moderate densities of binding sites were accompanied by a much more restricted expression of H2 receptor transcripts. Conversely, the mammillary region and the pontine nucleus exhibited higher levels of hybridization than of binding sites. In hippocampus, cerebral and cerebellar cortex there was a selective localization of the H2 receptor messenger RNA in the granule cells of dentate gyrus, pyramidal cells of the Ammon's horn and cerebral cortex, and Purkinje cells of cerebellum, whereas [(125)I]iodoaminopotentidine binding sites were located in layers where the dendritic trees of these messenger RNA-expressing neurons extend. The same discrepancy between messenger RNAs and binding sites suggests that striatonigral endings are endowed with the H2 receptor. The histamine H1 and H2 receptors both appear to be present in several brain areas, in some cases in a way suggesting their potential co-expression by the same neuronal populations, e.g., in granule and pyramidal cells in the hippocampal formation. This co-expression accounts for synergic responses, e.g., on cAMP generation, previously observed upon co-stimulation of both receptor subtypes. The widespread distribution of the H2 receptor, namely in thalamic nuclei or in telencephalic areas such as most layers of the cerebral cortex, together with its excitatory role previously established in electrophysiological studies, support its alleged function in mediating the histamine-driven control of arousal mechanisms. In addition, the detection of H2 receptor expression in brainstem areas from which other monoaminergic pathways involved in the control of states of sleep and wakefulness emanate, e.g., several raphe nuclei, locus coeruleus or substantia innominata, suggests possible interrelationships between all of these systems with highly divergent projections to the thalamus and telencephalon. The present mapping of the H2 receptor and its gene transcripts should facilitate neurochemical, neurophysiological and behavioural studies aimed at clarifying the role of histaminergic systems in brain.
- Published
- 1997
27. Mast cell specific proteases in rat brain: changes in rats with experimental allergic encephalomyelitis
- Author
-
A. Rouleau, G. F. J. Newlands, V. Dimitriadou, Monique Garbarg, H. R. P. Miller, M.D. Trung Tuong, and J.-C. Schwartz
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Encephalomyelitis, Autoimmune, Experimental ,Time Factors ,Encephalomyelitis ,Connective tissue ,In situ hybridization ,medicine ,Animals ,Mast Cells ,RNA, Messenger ,In Situ Hybridization ,Biological Psychiatry ,Immunoassay ,Neurons ,Thioperamide ,biology ,Serine Endopeptidases ,Degranulation ,Histaminergic ,Brain ,Mast cell ,medicine.disease ,Immunohistochemistry ,Rats ,Isoenzymes ,Psychiatry and Mental health ,medicine.anatomical_structure ,Neurology ,Rats, Inbred Lew ,biology.protein ,Neurology (clinical) ,Antibody ,Biomarkers ,Histamine ,medicine.drug - Abstract
Mast cell populations were identified within brain parenchyma by their specific proteases, using antibodies for immunohistochemistry and ELISAs, and riboprobes were developed for in situ hybridisation. Connective tissue mast cells expressing rat mast cell protease I (RMCPI) mRNA and immunoreactivity were observed in thalamus and showed no degranulation at 3, 8 and 13 days after induction of experimental allergic encephalomyelitis (EAE). Mucosal-like mast cells were clearly demonstrated in control rats by measuring RMCPII and by visualising cells expressing RMCPII mRNA and immunoreactivity. At day 13, but not 3 and 8 post immunisation, the number of RMCPII-expressing cells markedly increased in the EAE-induced group, mainly within brainstem and spinal cord close to inflammed blood vessels. The markers of histaminergic neurons were marginally affected 13 days after immunisation and the increase of [3H] histamine synthesis elicited by the H3-receptor antagonist, thioperamide, was not modified in any region of the brain. It is concluded that the cerebral RMCPII-expressing mast cells could play a role during EAE.
- Published
- 1997
28. Diphenylmethyl ethers: synthesis and histamine H3-receptor antagonist in vitro and in vivo activity
- Author
-
K. Purand, Holger Stark, X. Ligneau, Annette Hüls, Walter Schunack, J.M. Arrang, and J.-C. Schwartz
- Subjects
Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Antagonist ,Pharmaceutical Science ,Ether ,Biochemistry ,In vitro ,Propanol ,chemistry.chemical_compound ,chemistry ,In vivo ,Drug Discovery ,Molecular Medicine ,High activity ,Histamine H3 receptor ,Molecular Biology ,Histamine - Abstract
New potent histamine H3-receptor antagonists containing an ether group were synthesized from 3-(1H-imidazole-4-yl)propanol and various substituted diphenylmethyl chlorides. Some of the designed ethers showed high activity at histamine H3-receptors under in vitro as well as under in vivo conditions. Their activity at histamine H1- and H2-receptors was also investigated proving a pharmacological H 3 - H 1 - antagonistic profile.
- Published
- 1996
29. A radioimmunoassay for the tripeptide Gly-Trp-Met, a major metabolite of endogenous cholecystokinin in brain
- Author
-
Froylan Vargas, Bourgeat P, Christiane Rose, and J.-C. Schwartz
- Subjects
Isoflurophate ,Metabolite ,Radioimmunoassay ,Neuropeptide ,Endogeny ,Tripeptide ,Cross Reactions ,Sensitivity and Specificity ,Serine ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Endocrinology ,Benzoquinones ,Animals ,Amino Acid Sequence ,Derivatization ,Chromatography, High Pressure Liquid ,Cholecystokinin ,Cerebral Cortex ,Endocrine and Autonomic Systems ,Chemistry ,Sulfhydryl Reagents ,Reproducibility of Results ,General Medicine ,Hydrogen-Ion Concentration ,Rats ,Neurology ,Biochemistry ,Indicators and Reagents ,Oligopeptides - Abstract
We developed a specific and sensitive radioimmunoassay for the tripeptide Gly-Trp-Met (GWM) after its derivatization with p -benzoquinone. Measurable amounts of endogenous GWM-like immunoreactivity (GWM-ir), co-eluting in HPLC with authentic GMW were detected in the medium of depolarized slices of rat cerebral cortex. The tripeptide GWM appears as the major inactive CCK-8 metabolite since a major fraction of CCK-8-ir released from the slices was apparently recovered in the medium as GWM. In addition, in the presence of the serine reagent diisopropylfluorophosphate, a strong decrease of GWM formation was observed to accompany the corresponding increase of CCK-8-ir recovery in medium. The present study confirms that (a) serine peptidase(s) is(are) responsible for inactivating endogenous CCK-8 in brain as previously proposed (Rose et al. Proc Natl Acad Sci USA 1988; 85: 8326).
- Published
- 1996
30. [125I]Iodoproxyfan and Related Compounds: A Reversible Radioligand and Novel Classes of Antagonists with High Affinity and Selectivity for the Histamine H3 Receptor
- Author
-
J.‐C. Schwartz, Holger Stark, K. Purand, Annette Hüls, Walter Schunack, X. Ligneau, and M. Garbarg
- Subjects
Cerebral Cortex ,Stereochemistry ,Methylhistamines ,Guinea Pigs ,Histamine Antagonists ,Imidazoles ,Antagonist ,Muscarinic acetylcholine receptor M3 ,Ether ,In Vitro Techniques ,Radioligand Assay ,Rats ,Iodine Radioisotopes ,Structure-Activity Relationship ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Radioligand ,Animals ,Molecular Medicine ,Structure–activity relationship ,Histamine H3 receptor ,H3 receptor antagonist - Abstract
The synthesis and biological evaluation of new histamine H3 receptor antagonists with an iodinated aryl partial structure are described as part of an extensive research program to find model compounds for the development of a new radioligand with high H3 receptor affinity and specific activity. All compounds were tested for their H3 receptor antagonist activity in a [3H]-histamine-release assay with synaptosomes from rat cerebral cortex. The new leads with potent H3 receptor antagonist activity belong to a series of derivatives of 3-(1H-imidazol-4-yl)propanol with carbamate (4-7), ester (8-16), and ether (17-22) as functional groups. Structure-activity relationships are discussed. The most active compound in the functional test (-log Ki = 8.3) and in binding studies with [3H]-(R)-alpha-methylhistamine on rat cerebral cortex (-log Ki = 9.0) in vitro was 3-(1H-imidazol-4-yl)propyl (4-iodophenyl)methyl ether (iodoproxyfan, 19) exhibiting no central H3 receptor antagonist activity in vivo. The potency of iodoproxyfan is more than 300 times lower at H1, H2, alpha1, alpha2, beta1, 5-HT2A, 5-HT3, and M3 receptors than at histamine H3 receptors. Because of the high potency and selectivity of 19, this compound has also been prepared in the [125I]-iodinated form by a nucleophilic halogen exchange reaction using the corresponding bromo derivative 22 as a precursor. The newly prepared [125I]iodoproxyfan (23) possesses advantageous pharmacological properties and fulfills all criteria of a useful radioligand.
- Published
- 1996
31. Dopamine D3 receptor gene: Organization, transcript variants, and polymorphism associated with schizophrenia
- Author
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Nathalie Griffon, Antonia Mayerová, C. Pilon, Jean-Paul Macher, Marc-Antoine Crocq, Pierre Sokoloff, Marie-Pascale Martres, E. Burgert, F. Javoy-Agid, Fabrice Duval, J.-C. Schwartz, Gökhan Uyanik, and C. A. Tamminga
- Subjects
Genetics ,Exon ,Gene mapping ,Genotype ,Coding region ,Allele ,Gene mutation ,Restriction fragment length polymorphism ,Biology ,Genotyping ,Molecular biology ,Genetics (clinical) - Abstract
DNA fragments from a genomic library were used to establish the partial structure of the human dopamine D{sub 3} receptor gene (DRD3). Its coding sequence contains 6 exons and stretches over 40,000 base pairs. The complete DRD3 transcript and three shorter variants, in which the second and/or third exon are deleted, were detected in similar proportions in brains from four controls and three psychiatric patients. The Msp I polymorphism was localized in the fifth intron of the gene, 40,000 base pairs downstream the Bal I polymorphism and a PCR-based method was developed for genotyping this polymorphism. The distributions of the Msp I and Bal I genotypes were not independent in 297 individuals ({chi}{sup 2} = 10.5, df = 4, P = 0.03), but only a weak association was found between allele 1 of the Bal I polymorphism and allele 2 of the Msp I polymorphism ({chi}{sup 2} = 3.99, df = 1, P = 0.04). The previously reported association between homozygosity at both alleles of the Bal I polymorphism and schizophrenia was presently maintained in an extended sample, comprising 119 DSM-III-R chronic schizophrenics and 85 controls ({chi}{sup 2}= 5.3, df = 1, P = 0.02) and found more important inmore » males than in females. The presence of the Bal I allele 2 is associated with an early age at onset, particularly in males (df = 35, t value = 2.6, P = 0.014). In the same sample, allelic frequencies, genotype counts, and proportion of homozygotes for the Msp I polymorphism did not differ between schizophrenics and controls ({chi}{sup 2}= 0.06, df = 1, P = 0.80, {chi}{sup 2} = 0.22, df = 1, P = 0.90 and {chi}{sup 2} = 0.16, df = 1, P = 0.69, respectively). The large distance of the Msp I polymorphism from the Bal I polymorphism and its localization in the 3{prime} part of the gene may explain the discrepant results obtained with the two polymorphisms. 36 refs., 2 figs., 4 tabs.« less
- Published
- 1996
32. Functional models for the dopamine D3 receptor
- Author
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C. G. Wermuth, F. Sautel, C. Pilon, Pierre Sokoloff, J. Diaz, D. Levesque, P. Simon, J.-C. Schwartz, A. Mann, Nathalie Griffon, and J. Costentin
- Subjects
Pyrrolidines ,Quinpirole ,Receptors, Dopamine D2 ,Philosophy ,Receptors, Dopamine D3 ,Gene Expression ,Glioma ,Naphthalenes ,Transfection ,Models, Biological ,Biochemistry ,Nucleus Accumbens ,Recombinant Proteins ,Cell Line ,Neuroblastoma ,Dopamine receptor D3 ,Dopamine Agonists ,Cyclic AMP ,Animals ,Ergolines ,Cyclic AMP metabolism ,Humanities ,Cell Division ,Neurotensin - Abstract
Functional models for the dopamine D3 receptor N. Griffon*II, F. Sautel*, C. Pilon*, D. Levesque*, P. SokolofP, 1.-C. Schwartz*, J. Diazt, P. Simon*, J. Costentin*, A. Mann§ and C. G. Wermuthg *Unite de Neurobiologie et Pharrnacologie, Centre Paul Broca de I'INSERM, Paris, France, tLaboratoire de Physiologie, Universite Rene Descarte, Paris, France, SLaboratoire de Pharrnacologie et Physiologie, UER de Medecine et de Pharrnacie, Saint-Etienne du Rouvray, France, and SLaboratoire de Pharrnacologie Moleculaire, Centre de Neurochirnie, Strasbourg, France I93
- Published
- 1996
33. Novel Carbamates as Potent Histamine H3 Receptor Antagonists with High in Vitro and Oral in Vivo Activity
- Author
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J.‐C. Schwartz, Holger Stark, Walter Schunack, M. Garbarg, X. Ligneau, Jean-Michel Arrang, Agnès Rouleau, and K. Purand
- Subjects
Clobenpropit ,Guinea Pigs ,Histamine Antagonists ,Phenylcarbamates ,Administration, Oral ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,medicine ,Animals ,Receptors, Histamine H2 ,Receptors, Histamine H1 ,Cerebral Cortex ,Thioperamide ,Molecular Structure ,Chemistry ,Imidazoles ,Antagonist ,Burimamide ,In vitro ,Rats ,Biochemistry ,Molecular Medicine ,Carbamates ,Histamine H3 receptor ,Histamine ,Synaptosomes ,medicine.drug - Abstract
The known histamine H3 receptor antagonists burimamide, thioperamide, clobenpropit, and a related homohistamine thioamide derivative were taken as templates in search for new leads. Novel histamine H3 receptor antagonists structurally described as carbamate derivatives of 3-(1H-imidazol-4-yl)propanol were prepared in high yields by treatment of the alcohol with corresponding isocyanates or carbamoyl chlorides and investigated for their H3 receptor antagonist activity. Different chain lengths and various substituents possessing different electronic and steric parameters were introduced and structure-activity relationships established. In different functional tests, the new antagonists showed high H3 receptor antagonist potencies in vitro (-log Ki values of 6.4-8.4) at synaptosomes of rat cerebral cortex and low activities at histamine H1 and H2 receptor subtypes. They were also screened for their central in vivo activity in mice after peroral administration. The most promising compounds (2, 16, 19) showed ED(50) values of about 1-2 mg/kg and thus are potential drugs for the therapy of H3 receptor dependent diseases. Some of the novel carbamate derivatives are H3 receptor selective compounds with high in vitro and in vivo activity.
- Published
- 1996
34. Abstracts Second Congress of the European Society for Clinical Neuropharmacology
- Author
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G. Collingridge, D. Bruns, A. Teufel, P. Barbier, H. G. Bloß, K. P. Offord, C. Stahl-Hennig, E. N. H. Jansen, T. Sobanski, Carlo Ori, M. Goetz, A. Muratorio, Ulderico Freo, E. Sale, Eldad Melamed, J. M. Maloteaux, Z. Bashir, B. Guschelbauer, D. Fitzgeral, R. Korinthenberg, H. Baas, Armin Heils, I. M. Macrae, T. Kutschka, M. C. Anderson, M. Beeg, G. A. Wiesbeck, P. Del Dotto, P. C. O'Brien, J. Knauber, M. E. Götz, Keith F. Tipton, M. Simanyi, G. Rossi, Max Holzer, I. Svobodová, L. Mancino, L. Calza, Th. Müller, J. P. W. F. Lakke, Mauro Dam, A. Raja, Eri Hashimoto, F. Crépel, U. Pulkowski, R. Ceravolo, D. R. Schroeder, M. Streifler, L. L. Iversen, E. Lossmann, K. Lieb, F. Heinen, T. A. Ibrahim, M. Rösier, F. Siebecker, R. Schinzel, P. Emson, A. H. Rajput, C. H. Lücking, F. Ferraguti, D. Feineis, L. Froelich, Wolf-Dieter Heiss, Ewout R. Brunt, Oliver Griesbeck, N. Pavese, A. Gerstner, J. Putzke, U. Nöth, Paolo Maria Rossini, R. God, G.B. Cassano, R. Nafc, D. Müller, A. Cunningham, Daniela Necchi, Patrick Carroll, C. Lucetti, F. Abel, O. M. Adegemo, E. Braak, B. Molzer, N. Fichter, A. Lugowska, M. L. Rao, S. Roßner, F. Coraddu, A. Gemma, O. Tucha, L. J. Bryan-Lluka, I. Avdiunina, H. Beckmann, P. Fruth, H. W. Clement, F. Müller, E. de la Morena, W. Zieglgänsberger, A. P. Jeanjean, C. H. Lammers, A. Seghers, A. Nuti, A. Steup, M. Schwarz, Michael Sendtner, T. W. van Weerden, M. Li, B. Janetzky, R. Erdmann, R. Winkel, B. Niedermeyer, V. ter Meulen, M. Butà, D. Peckys, Th. Arendt, P. A. Löschmann, S. Strauss, D. Offen, B. Gangus, D. M. Yilmazer, K. Velbinger, T. J. Feuerstein, Klaus V. Toyka, R. S. J. Frackowiak, F. Conquet, K. Gasiorowski, F. Fascetti, C. Grote, A. Barzilai, Thomas A. Sontag, C. G. Parsons, G. Dell’Agnello, Hans-Peter Hartung, Toshikazu Saito, R. Stein, W. D. Rausch, E. Donati, P. Vanhoorde, S. Hartmann, E. Orlov, D. Inglot, Francesca Vaglini, W. Paulus, A. Merico, W. H. Jost, H. H. Borchert, M. Bagli, N. S. Alekseeva, T. Heinemann, B. K. Siesjö, T. Hirning, I. Ziv, C. Wurthman, M. J. Lohse, E. Hermsteiner, J. Coos Verhoef, B. Landwehrmeyer, Félix F. Cruz-Sánchez, Hans Lassmann, R. Jackisch, E. W. Fünfgeld, M. Naumann, Gilberto Pizzolato, M. Bigl, Helmut Heinsen, J. E. Ahlskog, M. Sieklucka, Hiroki Ozawa, S. Hesse, J. Pruim, H. E. Junginger, Andreas Moser, J. Boning, F. Fumagalli, M. Berger, M. Lauk, E. Borroni, M. Gerlach, M. Heider, C. Schwarzer, K. Jellinger, W. H. Oertel, S. Danielcyk, V. Tuulik, J. Bauer, F. Block, Udo Rüb, F. Böcker, Hans Thoenen, L. Komelkova, G. Zürcher, A. Hochman, A. Mesec, G. Jungkunz, G. Charles, P. Vieregge, P. Kalus, Jürgen Fritze, I. Faé, K. Eschrich, H. Standhardt, M. Schüler, W. Kolasiewicz, A. Meister, E. N. H. Janzen, M Melzacka, A. A. Sharkawy, Borwin Bandelow, M. Renna, S. Hauck, Marco A. Riva, U. Lockemann, R. M. Nitsch, Heiko Braak, R. Medori, S. Federspiel, J. Berger, D. Senitz, J. Wissel, Georg W. Kreutzberg, U. McMonagle, H. Przuntek, T. Reum, C. Heim, K. V. Morgunov, R. Maggio, J. Leszek, Gavin P. Reynolds, Gerald Münch, M. Klessaschek, B. Zielke, R. Morgenstern, P. A. Fischer, Y. Agid, B. Volk, H. Schuttes, Konstanze Plaschke, J. Krieglstein, Th. Büttner, D. Blum-Degen, Eleni Koutsilieri, N. Wodarz, Reinhard Schliebs, P. König, Klaus W. Lange, T. Motzek-Noé, Robert Jech, J. Niemann, M. Abdel-moneim, V. V. Peresedov, Juergen Deckert, G. Storm, S. Kamolz, W. Breithaupt, B. Weber, Giovanni Corsini, J. C. Schwartz, M. Hüll, C. Bancher, M. Struck, M. Abdel-mohsen, A. Napolitano, D. Labunsky, M. Sohlbach, T. Winter, J. Sautter, H. J. Degen, Y. Glinka, R. Dörries, C. D. Earl, R. Riederer, G. Bringmann, W. Kuhn, J. A. Protzen, M. Winter, T. Klockgether, B. Fiebich, O. S. Brusov, H. Daniel, B. Bethke, T. R. Tolle, A. Weindl, Michael Bauer, N. Takahata, A. Baumer, Isabella Heuser, V. Gieselmann, Gian Franco Placidi, Giulio Perugi, H. Bönisch, A. Eckert, J. Michaelis, F. von Raison, V. Bigl, S. Harder, Graziella Bernocchi, J. Kuijpers, R. Brückner, U. Bonuccelli, M. José Barro, G. Laux, S. Grüter, W. Retz, M. L. Mimmack, A. Kupsch, Austin Smith, I. Zhirnova, A. M. Sardar, A. I. Svadovsky, Siegfried Hoyer, Peter Riederer, B. Haug, Thomas Arzberger, H. Bernheimer, M. Seemann, Karl-Heinz Sontag, D. Bengel, L. Demisch, W. Danielczyk, Bettina Holtmann, Ullrich Wüllner, E. Hermans, E. V. Khrapova, G. B. Landwehrmeyer, A. Tylki-Szymanska, R. Brinkmann, F. Remeš, B. Kanner, S. L. Timerbaeva, P. Piccini, Susanne Petri, W. Wesemann, G. Ulmar, F. Rausch, Leontino Battistin, U. Ziemann, H. B. Pollard, Gerhard Ransmayr, P. Mečíř, C. Mattern, U. Gärtner, S. Sopper, Moussa B.H. Youdim, Michael Deuschle, M. Pozza, H. Schubert, G. Goping, Rainer Spanagel, Lutz Frölich, L. HaveIec, Martina K. Brückner, W. Gsell, Werner Poewe, M. Da Prada, J. Hartmann, H. J. Stürenburg, B. Löschl, M. Norta, J. Dichgans, G. Stern, J. Mayr, Elda Scherini, D. Bleyl, A. Colzi, P. Rosario, C. D'Avino, J. X Xie, Klaus-Peter Lesch, M. Demuth, M. Ymamoto, A. Toso, K. Lehmann, F. Eblen, J. Thome, R. Burger, S. Šega, G. Farci, Evžen Růžička, F. W. H. M. Merkus, I. Strein, M. Rösler, T. Jaros, D. Barletta, W. W. Chan, U. Havemann-Reinecke, T. Kiauta, R. A. I. de Vos, S. Fähr, A. Körner, A. J. Willemsen, P. J. Neveu, A. V. Moshkin, A. Kleinschroth, L. A. Avdyuna, Johannes Kornhuber, Ryan J. Uitti, R. Häcker, Jan Roth, E. C. Laterre, H. Sternadl, Amos D. Korczyn, G. Künig, Werner E.G. Müller, W. Berger, G. Racagni, S. Salvetti, G. M. Emilien, Parsadanian As, K. Kunze, G. Sperk, D. Högemann, H. Maier, S. Behrens, D. K. Teherani, C Pardini, Karlheinz Reiners, T. S. Chen, C. J. Eggett, L. Popova, H. Reichmann, J. M. Rabey, H. Hartmann, Arvid Carlsson, B. Lawlor, F. Bürklin, O. Gleichauf, and S. Hemm
- Subjects
0303 health sciences ,medicine.medical_specialty ,Public health ,03 medical and health sciences ,Psychiatry and Mental health ,0302 clinical medicine ,Neurology ,medicine ,Neurology (clinical) ,Psychiatry ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,Biological Psychiatry ,Neuropharmacology ,030304 developmental biology - Published
- 1995
35. The D3 receptor and its relevance in psychiatry
- Author
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J C Schwartz, N Griffon, J Diaz, D Levesque, F Sautel, P Sokoloff, P Simon, J Costentin, F Garrido, A Mann, and C Wermuth
- Subjects
medicine.medical_specialty ,Antagonist ,Nafadotride ,Nucleus accumbens ,Psychiatry and Mental health ,chemistry.chemical_compound ,chemistry ,Dopamine receptor D3 ,Dopamine ,Dopamine receptor D2 ,medicine ,Pharmacology (medical) ,Receptor ,Psychiatry ,Neurotensin ,medicine.drug - Abstract
A large fraction of neurotensin neurons in the ventromedial shell subdivision of nucleus accumbens express D3 receptors. Blockade of D2/D3 receptors by antipsychotic agents paradoxically decreases neurotensin gene expression in these neurons whereas it enhances it in other striatal areas expressing the D2 receptor. This suggests that D2 and D3 receptors mediate opposite actions of dopamine. In support of this view low doses of nafadotride, a novel D3 receptor-preferring antagonist, enhances locomotor activity in rodents, a behavioral response opposite to that of current neuroleptics. The action of D3 receptor-preferring agonists was characterized by the mitogenic response they elicit in transfected NG 108-15 cells. Finally, gene expression of the D3 receptor is in opposition to that of the D2 receptor, being decreased by denervation and unaffected by chronic blockade by neuroleptics.
- Published
- 1995
36. Phenotypical characterization of neurons expressing the dopamine D3 receptor in the rat brain
- Author
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Marie-Pascale Martres, C.H. Lammers, Nathalie Griffon, J.-C. Schwartz, Pierre Sokoloff, D. Levesque, and Jorge Diaz
- Subjects
Male ,Tetrahydronaphthalenes ,Tyrosine 3-Monooxygenase ,Gene Expression ,Nucleus accumbens ,Biology ,Nucleus Accumbens ,Receptors, Dopamine ,Ventral pallidum ,Dopamine receptor D1 ,Dopamine receptor D3 ,Dopamine ,Dopamine receptor D2 ,medicine ,Animals ,RNA, Messenger ,Rats, Wistar ,In Situ Hybridization ,Neurons ,Binding Sites ,General Neuroscience ,Rats ,Cell biology ,Substantia Nigra ,Ventral tegmental area ,medicine.anatomical_structure ,nervous system ,Islands of Calleja ,Autoradiography ,Neuroscience ,medicine.drug - Abstract
We have established the cellular distribution of the dopamine D3 receptor using tritiated 7-hydroxy-N-N-di-n-propyl-2-aminotetralin and a complementary RNA probe to visualize autoradiographically the protein in binding studies and the gene transcripts by in situ hybridization, respectively. Studies with these two markers confirm the restricted expression of the D3 receptor in few brain areas, i.e. mainly the ventral striatal complex, the substantia nigra-ventral tegmental area and the cerebellum. In nucleus accumbens, the D3 receptor was mainly expressed in medium-sized neurons of the rostral pole and ventromedial shell subdivisions, but not of the core or septal pole, i.e. accumbal subdivisions expressing the D2 receptor. In the ventromedial shell, about 60% of the D3 receptor-expressing neurons were neurotensin neurons, presumably projecting to the ventral pallidum. In the islands of Calleja, both D3 receptor binding and messenger RNA were abundant in the entire population of granule cells. These cells are known to make sparse contacts with dopaminergic axons and also to express the D1 receptor. In the mesencephalon, low levels of D3 messenger RNA were detected in few dopamine neurons of substantia nigra pars lateralis and ventral tegmental area. In addition, some D3 receptor binding but not messenger RNA was detected in medial substantia nigra and lateral ventral tegmental area, where the receptor is presumably located presynaptically on afferents. In the archicerebellum, Purkinje cell perikarya in lobules 9 and 10 expressed the D3 receptor messenger RNA, whereas binding sites were found in the molecular layer, where corresponding dendrites but no known dopaminergic projection from mesencephalon are found. The occurrence of D3 receptor gene expression in some brain areas receiving low dopamine innervation supports the hypothesis that this receptor may mediate non-synaptic actions of dopamine.
- Published
- 1995
37. Characterization of a serine peptidase responsible for the inactivation of endogenous cholecystokinin in human brain
- Author
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J.-C. Schwartz, Froylan Vargas, Devaux B, Silhouette B, and Christiane Rose
- Subjects
Thiorphan ,Isoflurophate ,Molecular Sequence Data ,Neuropeptide ,Nerve Tissue Proteins ,Peptide ,Endogeny ,Biology ,Aminopeptidases ,Sincalide ,Serine ,Cellular and Molecular Neuroscience ,Endocrinology ,Leucine ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Serpins ,Cholecystokinin ,Cerebral Cortex ,chemistry.chemical_classification ,Endocrine and Autonomic Systems ,Serine Endopeptidases ,General Medicine ,Human brain ,Rats ,Enzyme ,medicine.anatomical_structure ,Neurology ,Biochemistry ,chemistry ,Neprilysin ,medicine.drug - Abstract
Depolarization of slices of human cerebral cortex releases cholecystokinin-8 immunoreactivity, only a fraction of which is recovered in intact immunoreactive form in the medium. This suggests that extensive hydrolysis takes place during short incubations. In the presence of diisopropylfluorophosphate, a serine reagent, the recovery is nearly doubled, however, consistent with the involvement of a serine peptidase activity. The latter was characterized by assessing the protective effects of a series of serine protease inhibitors belonging to the families of peptide chloromethylketones or boronic acids. The relative potency of these inhibitors was similar to corresponding values previously found with rat brain slices indicating that a similar serine peptidase activity is responsible for endogenous cholecystokinin inactivation in the two species.
- Published
- 1995
38. Signaling Mechanisms of D2, D3, and D4 Dopamine Receptors Determined in Transfected Cell Lines
- Author
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H. H. M. Van Tol, Marc G. Caron, M. F. Piercey, M. E. Lajiness, C. L. Chio, C. A. Tamminga, A. Carlsson, J. C. Schwartz, and Rita M. Huff
- Subjects
Pharmacology ,Biochemistry ,Chemistry ,G protein ,Dopamine receptor ,Cell culture ,Pharmacology (medical) ,Neurology (clinical) ,Transfection - Published
- 1995
39. Localization, Regulation, and Role of the Dopamine D3 Receptor Are Distinct from Those of the D2 Receptor
- Author
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Pierre Sokoloff, Fabrice Garrido, D. Levesque, Piercey, Jean Costentin, Willner, C. C. Wermuth, J. Diaz, F. Sautel, Huff, J.-C. Schwartz, P. Simon, Carlsson, Van Tol, A. Mann, and Nathalie Griffon
- Subjects
Pharmacology ,Central nervous system ,Biology ,medicine.anatomical_structure ,Mechanism of action ,Dopamine receptor D3 ,Dopamine receptor D2 ,Gene expression ,medicine ,Enzyme-linked receptor ,Pharmacology (medical) ,Neurology (clinical) ,medicine.symptom ,Neuroscience - Published
- 1995
40. Preclinical evaluation of the abuse potential of Pitolisant, a histamine H₃ receptor inverse agonist/antagonist compared with Modafinil
- Author
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M, Uguen, D, Perrin, S, Belliard, X, Ligneau, P M, Beardsley, J M, Lecomte, and J C, Schwartz
- Subjects
Male ,Behavior, Animal ,Dose-Response Relationship, Drug ,Drug Inverse Agonism ,Dopamine ,Dopaminergic Neurons ,Drug Evaluation, Preclinical ,Histamine Antagonists ,Modafinil ,Drugs, Investigational ,Wakefulness-Promoting Agents ,Motor Activity ,Macaca mulatta ,Research Papers ,Nucleus Accumbens ,Rats ,Behavior, Addictive ,Histamine Agonists ,Mice ,Piperidines ,Animals ,Receptors, Histamine H3 ,Central Nervous System Stimulants ,Benzhydryl Compounds ,Drug Antagonism - Abstract
Pitolisant, a histamine H₃ receptor inverse agonist/antagonist is currently under Phase III clinical trials for treatment of excessive daytime sleepiness namely in narcoleptic patients. Its drug abuse potential was investigated using in vivo models in rodents and monkeys and compared with those of Modafinil, a psychostimulant currently used in the same indications.Effects of Pitolisant on dopamine release in the nucleus accumbens, on spontaneous and cocaine-induced locomotion, locomotor sensitization were monitored. It was also tested in three standard drug abuse tests i.e. conditioned place preference in rats, self-administration in monkeys and cocaine discrimination in mice as well as in a physical dependence model.Pitolisant did not elicit any significant changes in dopaminergic indices in rat nucleus accumbens whereas Modafinil increased dopamine release. In rodents, Pitolisant was without any effect on locomotion and reduced the cocaine-induced hyperlocomotion. In addition, no locomotor sensitization and no conditioned hyperlocomotion were evidenced with this compound in rats whereas significant effects were elicited by Modafinil. Finally, Pitolisant was devoid of any significant effects in the three standard drug abuse tests (including self-administration in monkeys) and in the physical dependence model.No potential drug abuse liability for Pitolisant was evidenced in various in vivo rodent and primate models, whereas the same does not seem so clear in the case of Modafinil.
- Published
- 2012
41. Unsymmetrically substituted guanidines as potent histamine H3-receptor antagonists
- Author
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J.-C. Schwartz, Holger Stark, X. Ligneau, M. Krause, Walter Schunack, and J.M. Arrang
- Subjects
chemistry.chemical_classification ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Prodrug ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Molecular Medicine ,Histamine H3 receptor ,Guanidine ,Molecular Biology ,Guanidine derivatives ,Histamine ,Alkyl - Abstract
Unsymmetrically trisubstituted and disubstituted guanidine derivatives of (1H-imidazol-4-yl)alkyl amines were synthesized and investigated for histamine H3-receptor activity. Electron-withdrawing substitution of the guanidino group resulted in antagonists with a potential prodrug character. The H3-receptor selective N1-cyclohexylmethyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidine possesses a -log Ki of 9.1.
- Published
- 1994
42. Functional Relationship between Mast Cells and C-Sensitive Nerve Fibres Evidenced by Histamine H3-Receptor Modulation in Rat Lung and Spleen
- Author
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A. Rouleau, G. Luffau, J.-C. Schwartz, G. J. F. Newlands, H. R. P. Miller, V. Dimitriadou, Monique Garbarg, and M. Dam Trung Tuong
- Subjects
Male ,medicine.medical_specialty ,Calcitonin Gene-Related Peptide ,Spleen ,Biology ,Calcitonin gene-related peptide ,Feedback ,chemistry.chemical_compound ,Chymases ,Nerve Fibers ,Internal medicine ,medicine ,Animals ,Receptors, Histamine H3 ,Mast Cells ,Histamine H4 receptor ,Rats, Wistar ,Lung ,Strongylida Infections ,Neurogenic inflammation ,Thioperamide ,Serine Endopeptidases ,General Medicine ,Mast cell ,Rats ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Capsaicin ,Histamine H3 receptor ,Histamine ,medicine.drug - Abstract
1. Mast cell populations in rat lung and spleen were characterized by the presence of two specific protease markers, rat mast cell protease I and II, using both histochemical and radioimmunoassay techniques. Three mast cell populations with different size, morphology and localization were found in lung and spleen and were identified according to the expression of rat mast cell protease I (RMCPI+) or rat mast cell protease II (RMCPII+) or of both proteases (RMCPI/II+). 2. All three mast cell types were in the vicinity of calcitonin-gene-related-peptide-immunoreactive (CGRP+) nerve fibres in controls as well as in rats infected by Nippostrongylus brasiliensis in which a large increase in the number of both RMCPII+ and RMCPI/II+ mast cells was found. Ablation of the CGRP+ fibres by neonatal treatment with capsaicin resulted in a marked increase in the number of RMCPII+ and RMCPI/II+ cells in lung and, even more, in spleen of adult rats. 3. The interaction of mast cells with CGRP+ C-fibres was assessed pharmacologically by evaluation of the effects of histamine H3-receptor ligands known to act on various types of nerve endings, including those of C-fibres. The effects of H3-receptor ligands were assessed in controls, nematode-infected rats and neonatally capsaicinized rats. Mast cell activity was evaluated by measurement of [3H]histamine synthesis from [3H]histidine. In control rats, administration of the H3-receptor agonist (R)-α-methylhistamine and antagonist thioperamide, decreased and enhanced respectively [3H]histamine synthesis in lung and spleen, indicating a tonic control of mast cell activity by histamine via H3-receptors. Such effects were not found in the jejunum, although RMCPII+ mast cells are in close apposition with neuropeptide-containing fibres. The effects of the H3-receptor agents were maintained in lung and spleen of nematode-infected rats, but were almost suppressed in capsaicinized rats. 4. It is concluded that the control of mast cells by histamine acting at H3-receptors involves neuropeptide-containing nerves and presumably reflects the operation of a local neuron-mast cell feedback loop controlling processes such as ‘neurogenic inflammation’. This loop still functions when mast cells proliferate in an inflammatory condition. These observations suggest that the use of histamine H3-receptor agonists may constitute a novel therapeutic approach to limit excessive inflammatory responses resulting from dysregulation of this feedback loop.
- Published
- 1994
43. Opposing Roles for Dopamine D2and D3Receptors on Neurotensin mRNA Expression in Nucleus Accumbens
- Author
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Pierre Sokoloff, D. Levesque, Jorge Diaz, Marie-Pascale Martres, J.-C. Schwartz, C.H. Lammers, and Nathalie Griffon
- Subjects
Male ,medicine.medical_specialty ,Transcription, Genetic ,medicine.drug_class ,Nucleus accumbens ,Nucleus Accumbens ,Receptors, Dopamine ,chemistry.chemical_compound ,Dopamine receptor D1 ,Dopamine receptor D3 ,Internal medicine ,Dopamine receptor D2 ,medicine ,Animals ,RNA, Messenger ,Rats, Wistar ,Receptor ,Neurotensin ,SCH-23390 ,Receptors, Dopamine D2 ,Chemistry ,General Neuroscience ,Receptors, Dopamine D3 ,Benzazepines ,Receptor antagonist ,Rats ,Endocrinology ,Haloperidol ,Sulpiride - Abstract
Using in situ hybridization histochemistry in rat nucleus accumbens, we show that the dopamine D3 receptor mRNA is expressed in the ventromedial part of the shell subdivision, where its gross distribution matches that of neurotensin mRNA. In addition, hybridization studies at the cellular level show that a large fraction of the neurotensin neurons co-express the D3 receptor mRNA in this restricted area. In contrast, the dopamine D2 receptor mRNA is expressed mainly in the core and marginally in the shell, at the level of the cone. In rats treated by haloperidol and sulpiride, two D2-like receptor antagonists, but not by SCH 23390, a D1-like receptor antagonist, proneurotensin mRNA was increased in the D2 receptor mRNA-rich areas but decreased in the D3 receptor mRNA-rich areas. This suggests that the D2 and D3 receptors control neurotensin mRNA expression negatively and positively, respectively.
- Published
- 1994
44. Molecular Cloning of Rat Mast Cell Protease 1 and Development of Specific Probes for Its Gene Transcript
- Author
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J.-C. Schwartz, A. Rouleau, Martial Ruat, Monique Garbarg, PERIGNON, Alain, Unité de Neurobiologie et Pharmacologie Moléculaire [Centre Paul Broca] (U109 INSERM ), and Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Male ,Transcription, Genetic ,MESH: Sequence Homology, Amino Acid ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,medicine.medical_treatment ,MESH: Chymases ,[SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior ,Gene Expression ,MESH: Amino Acid Sequence ,MESH: Base Sequence ,Polymerase Chain Reaction ,Biochemistry ,Gene expression ,MESH: Animals ,Mast Cells ,MESH: Serine Endopeptidases ,Cloning, Molecular ,Peptide sequence ,chemistry.chemical_classification ,[SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior ,Serine Endopeptidases ,MESH: Tongue ,Nucleic acid sequence ,[SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences ,MESH: Mast Cells ,Amino acid ,Isoenzymes ,Jejunum ,MESH: Isoenzymes ,MESH: Protein Sorting Signals ,MESH: DNA Primers ,Proteases ,MESH: Gene Expression ,MESH: Rats ,Molecular Sequence Data ,Biophysics ,Protein Sorting Signals ,Biology ,Molecular cloning ,Chymases ,Tongue ,Complementary DNA ,medicine ,Animals ,MESH: Blotting, Northern ,MESH: Cloning, Molecular ,Amino Acid Sequence ,RNA, Messenger ,Rats, Wistar ,Molecular Biology ,DNA Primers ,MESH: RNA, Messenger ,MESH: Molecular Sequence Data ,Protease ,Base Sequence ,Sequence Homology, Amino Acid ,MESH: Transcription, Genetic ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,MESH: Polymerase Chain Reaction ,MESH: Rats, Wistar ,Cell Biology ,Blotting, Northern ,Molecular biology ,MESH: Male ,Rats ,chemistry ,MESH: Jejunum ,[SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences - Abstract
International audience; Rat mast cell protease of type 1 (RMCP1) is a specific marker of connective tissue mast cells selectively occurring in some tissues, e.g., the tongue. Its amino acid sequence is known (Le Trong et al., Biochem. 1987, 26, 6988-6994) but not the corresponding nucleotide sequence. Amplification of mRNAs from rat tongue was performed by reverse transcriptase-polymerase chain reaction (RT-PCR) using oligonucleotide primers corresponding to the translated region of rat mast cell protease 2 (RMCP2) gene. The cDNA obtained was subcloned and sequenced, leading to an amino acid sequence which matched the known 227 amino acid sequence. In addition there was, however, two sequences of 11 amino acids at the N-terminus and 13 amino acids at the C-terminus. The amino acid identity was of 74% with RMCP2, and of 76%, 65% and 90% with the mouse proteases MMCP1, MMCP2 and MMCP4, respectively. Based on the sequence of RMCP1 or RMCP2 cDNAs, selective oligoprobes were designed and their specificity established by Northern blot analysis of mRNAs purified from tongue and jejunum, two tissues containing selectively type 1 and 2 protease, respectively. Single 1.2 and 1.0 kb transcripts were evidenced in tongue and jejunum, respectively. In addition, a RT-PCR method was developed to amplify selectively each transcript which may serve as reliable markers in the analysis of mast cell heterogeneity, differentiation and function.
- Published
- 1994
45. Acylated and alkylated histamine derivatives as new histamine H3-receptor antagonists
- Author
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Holger Stark, J.M. Arrang, J.-C. Schwartz, Ralph Lipp, Walter Schunack, and Monique Garbarg
- Subjects
Pharmacology ,medicine.drug_class ,Stereochemistry ,Organic Chemistry ,Antagonist ,Biological activity ,Carboxamide ,General Medicine ,Alkylation ,chemistry.chemical_compound ,chemistry ,Amide ,Drug Discovery ,medicine ,Methylene ,Histamine H3 receptor ,Histamine - Abstract
New histamine H3-receptor antagonists were prepared and investigated for their ability to increase synthesis and release of histamine mediated by inhibition of presynaptically located H3-receptors. Acyl derivatives of histamine methylated at different positions show poor activity at H3-receptors, whereas Nα-alkyl and particularly Nα-acyl derivatives of histamine possess moderate to good H3-receptor antagonist activity. A not-too-bulky and lipophilic residue in an optimal distance of 3–4 methylene groups from the amide function leads to potent and selective H3-receptor antagonists. Nα-Histamine-γ-phenylbutyramide II and Nα-histamine-γ-cyclohexylbutyramide 13 are H3-receptor antagonists with — log Ki of 7.1 and 7.3, respectively. Structure-activity relationships of different substitution patterns are discussed.
- Published
- 1994
46. Loss of striatal histamine H2receptors in Huntington's: Chorea but not in Parkinson's disease: Comparison with animal models
- Author
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Martial Ruat, Hélène Pollard, M. I. Martinez-Mir, J.-C. Schwartz, José Palacios, Elisabeth Traiffort, and J. Moreau
- Subjects
medicine.medical_specialty ,Putamen ,Chorea ,Substantia nigra ,Biology ,nervous system diseases ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Endocrinology ,Globus pallidus ,nervous system ,Histamine H2 receptor ,chemistry ,Internal medicine ,Basal ganglia ,medicine ,medicine.symptom ,Histamine ,Quinolinic acid - Abstract
Autoradiographic techniques were used to study the distribution of histamine H2-receptors as labeled with [125I]iodoaminopotentidine in the brains of patients affected by human neurodegenerative pathologies, as compared with control cases. The highest levels of histamine H2 binding sites in control cases were found in the caudate, putamen, and accumbens nuclei. In Huntington's chorea, the levels of histamine H2 receptor binding sites were found to be markedly decreased in virtually all regions examined, particularly in the putamen and globus pallidus lateralis. The loss of binding sites was related to the grade of the disease. Losses were more marked in grade III disease cases. The possible influence of neuroleptic treatment, commonly used in Huntington's patients, was studied by including samples from clinically treated schizophrenic patients. A moderate increase in the densities of [125I]iodoaminopotentidine was found in the globus pallidus of these patients. In Parkinson's disease, the levels of histamine H2-receptor binding sites were found not to be significantly different from those of control cases. These results were comparable with those obtained from unilaterally neurotoxin-lesioned guinea pigs. Similar losses of binding sites were observed in the quinolinic acid lesioned striatal intrinsic neurons in the guinea pig, whereas lesioning dopaminergic cell bodies in the substantia nigra with 6-hydroxydopamine did not produce any significant change. These results strongly suggest that histamine H2-receptors are expressed by striatal neurons, which degenerate in Huntington's chorea, but not by nigral dopaminergic neurons and may play a role in the regulation of the intact striato-nigral pathway. © 1993 Wiley-Liss, Inc.
- Published
- 1993
47. A detailed autoradiographic mapping of histamine H3 receptors in rat brain areas
- Author
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J.-C. Schwartz, Hélène Pollard, J. Moreau, and J.M. Arrang
- Subjects
Male ,medicine.medical_specialty ,Kainic acid ,Striatum ,Histidine Decarboxylase ,Nucleus accumbens ,Biology ,Histamine Agonists ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Receptors, Histamine H3 ,Rats, Wistar ,Brain Mapping ,Basal forebrain ,Kainic Acid ,Methylhistamines ,General Neuroscience ,Medial Forebrain Bundle ,Histaminergic ,Brain ,Rats ,Endocrinology ,medicine.anatomical_structure ,Globus pallidus ,nervous system ,chemistry ,Cerebral cortex ,Hypothalamic Area, Lateral ,Autoradiography ,Receptors, Histamine ,Histamine H3 receptor - Abstract
[ 3 H]( R )α-methylhistamine, a selective histamine H 3 -receptor ligand, was used to perform binding studies with membranes and generate light microscopic autoradiograms in sections of the rat brain. High densities of H 3 receptors were found in membranes from the anterior part of the cerebral cortex, the accumbens nucleus, the striatum, the olfactory tubercles and the substantia nigra. Autoradiography of sagittal and frontal sections evidenced specific labelling in a number of gray matter areas over a very low background, as determined using thioperamide, a selective H 3 -receptor antagonist, as competing drug. Labelled areas were identified by comparison with adjacent Nissl-stained sections and their labelling was rated visually. H 3 receptors are heterogeneously distributed among areas known to receive histaminergic projections. In the cerebral cortex, H 3 receptors are present in all areas and layers, with a rostrocaudal gradient and a higher density in deep layers (laminae IVV¯I). In the hippocampal formation, H 3 receptors are the most abundant in the dentate gyrus and the subiculum. In the amygdaloid complex, the highest densities are found in the central, lateral and basolateral groups of nuclei. In the basal forebrain, the accumbens nucleus, the striatum, the olfactory tubercles and the globus pallidus are highly labelled. In the thalamus in which histaminergic fibres are scarce, H 3 receptors are present in a rather high density, particularly in the midline, median and intralaminar groups of nuclei. In the hypothalamus, where the densest network of histaminergic fibres is found, H 3 receptors occur in moderate density, being slightly more abundant in the anterior and medial part. They are also present at the level of the tuberomammillary nuclei where they may reside on histaminergic perikarya. In mesencephalon and lower brainstem, H 3 receptors are abundant in the reticular part of the substantia nigra and central gray. They are present in low density in areas of noradrenergic and serotoninergic perikarya and in the spinal cord, where a faint specific labelling is detected in the gray matter, particularly in the external layers of the dorsal horn. In the cerebellum and pituitary gland, H 3 receptors are scarce. Kainic acid infusions into the striatum were followed by marked local decreases in H 3 receptors evidenced in both membrane binding and autoradiographic studies. Unilateral interruption of the ascending histaminergic pathways via electrocoagulation of the lateral hypothalamic area was followed by ipsilateral increase in striatal [ 3 H]( R )α-methylhistamine binding, a process consistent with denervation up regulation of postsynaptic H 3 receptors. These lesion data, taken together with the differences observed between the regional distribution of H 3 receptors and that of histaminergic axons, indicate that these receptors are more abundant on target cells than on histaminergic neurons where they act as autoreceptors.
- Published
- 1993
48. ChemInform Abstract: Synthesis, X-Ray Crystallography, and Pharmacokinetics of Novel Azomethine Prodrugs of (R)-α-Methylhistamine: Highly Potent and Selective Histamine H3 Receptor Agonists
- Author
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M. Garbarg, A. Rouleau, M. Krause, Walter Schunack, Peter Luger, Ralph Lipp, Holger Stark, and J.‐C. Schwartz
- Subjects
Histamine H3 Receptor Agonists ,Pharmacokinetics ,Stereochemistry ,Chemistry ,X-ray crystallography ,Methylhistamine ,General Medicine ,Prodrug ,Combinatorial chemistry - Published
- 2010
49. ChemInform Abstract: Diphenylmethyl Ethers: Synthesis and Histamine H3-Receptor Antagonist in vitro and in vivo Activity
- Author
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Holger Stark, X. Ligneau, Walter Schunack, J.‐C. Schwartz, J.‐M. Arrang, K. Purand, and A. Huels
- Subjects
In vivo ,Chemistry ,Antagonist ,General Medicine ,Pharmacology ,Histamine H3 receptor ,In vitro - Published
- 2010
50. ChemInform Abstract: Novel Histamine H3-Receptor Antagonists with Benzyl Ether Structure or Related Moieties: Synthesis and Structure-Activity Relationships
- Author
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K. Purand, J.‐M. Arrang, X. Ligneau, J.‐C. Schwartz, A. Huels, Holger Stark, Walter Schunack, and S. Reidemeister
- Subjects
Benzyl ether ,Chemistry ,Stereochemistry ,Organic chemistry ,General Medicine ,Histamine H3 receptor - Published
- 2010
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