56 results on '"Karen L. Marquis"'
Search Results
2. Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors
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Albert J. Robichaud, Norbert Hoefgen, Karen L. Marquis, Steven M. Grauer, Hans Stange, Radka Graf, Ute Egerland, Thorsten Hage, Christian Grunwald, Julie A. Brennan, Michael S. Malamas, Boyd L. Harrison, Menelas N. Pangalos, Kevin Parris, Thomas Kronbach, Yike Ni, Kristi Fan, Rudolf Schindler, Rachel Navarra, Hans-Joachim Lankau, Nicholas J. Brandon, James Joseph Erdei, and Barbara Langen
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Male ,Models, Molecular ,Phosphodiesterase Inhibitors ,Protein Conformation ,Stereochemistry ,Administration, Oral ,Stereoisomerism ,Hyperkinesis ,In Vitro Techniques ,Crystallography, X-Ray ,Ligands ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,Dogs ,Microsomes ,Drug Discovery ,Avoidance Learning ,Cyclic AMP ,Animals ,Humans ,Structure–activity relationship ,Potency ,Rats, Wistar ,Binding site ,Cyclic GMP ,ADME ,chemistry.chemical_classification ,Binding Sites ,Phosphoric Diester Hydrolases ,Hydrolysis ,Phosphodiesterase ,Recombinant Proteins ,Rats ,Isoenzymes ,Enzyme ,chemistry ,Pyrazines ,Molecular Medicine ,Female ,PDE10A ,Stereotyped Behavior ,Antipsychotic Agents - Abstract
The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.
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- 2011
3. Discovery of Imidazo[1,5-a]pyrido[3,2-e]pyrazines as a New Class of Phosphodiesterase 10A Inhibitiors
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Thorsten Hage, Nicholas J. Brandon, Norbert Höfgen, Hans-Joachim Lankau, Menelas N. Pangalos, Christian Grunwald, Karen L. Marquis, Michael S. Malamas, Rudolf Schindler, Thomas Kronbach, Hans Stange, Peter Tremmel, Barbara Langen, Ute Egerland, and Boyd L. Harrison
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Models, Molecular ,Quantitative structure–activity relationship ,Phosphodiesterase Inhibitors ,Phosphoric Diester Hydrolases ,Protein Conformation ,Stereochemistry ,Chemistry ,Quantitative Structure-Activity Relationship ,Phosphodiesterase ,In vitro ,Rats ,Stereotypy (non-human) ,Pyrazines ,Drug Discovery ,Hydrolase ,Animals ,Humans ,Molecular Medicine ,Female ,PDE10A ,Rats, Wistar ,Binding site - Abstract
Novel imidazo[1,5-a]pyrido[3,2-e]pyrazines have been synthesized and characterized as both potent and selective phosphodiesterase 10A (PDE10A) inhibitors. For in vitro characterization, inhibition of PDE10A mediated cAMP hydrolysis was used and a QSAR model was established to analyze substitution effects. The outcome of this analysis was complemented by the crystal structure of PDE10A in complex with compound 49. Qualitatively new interactions between inhibitor and binding site were found, contrasting with previously published crystal structures of papaverine-like inhibitors. In accordance with the known antipsychotic potential of PDE10A inhibitors, MK-801 induced stereotypy and hyperactivity in rats were reversed by selected compounds. Thus, a promising compound class has been identified for the treatment of schizophrenia that could circumvent side effects connected with current therapies.
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- 2010
4. Temporal dysregulation of cortical gene expression in the isolation reared Wistar rat
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Nanette Rombach, Robert H. Ring, Caitlin Wantuch, Darren Scully, Andrew W. Cassidy, Olive McCabe, Zoë A. Hughes, Rocio Fedriani, Menelas N. Pangalos, Angela T. Brady, Paul A. McGettigan, Mary P. Moran, Ciaran M. Regan, S.K. Mulvany, Christine Li, Niamh C. O’Sullivan, Jennifer S. Loscher, William T. O'Connor, Keith J. Murphy, Joanna Connellan, Desmond G. Higgins, Ian E. J. DeSouza, David von Schack, Bartlomiej Lukasz, Laura M. Connole, Karen L. Marquis, Judith P. F. Ter Horst, and Marina Morgunova
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Male ,Microdialysis ,GABRA4 ,Hypofrontality ,Motor Activity ,Biochemistry ,RNA, Complementary ,Synapse ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Glutamatergic ,Neurochemical ,Animals ,Rats, Wistar ,Neurotransmitter ,Prefrontal cortex ,Oligonucleotide Array Sequence Analysis ,Cerebral Cortex ,Behavior, Animal ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Computational Biology ,DNA ,Rats ,Gene Expression Regulation ,Social Isolation ,chemistry ,Multigene Family ,Synapses ,biology.protein ,RNA ,Neuroscience ,Immediate early gene ,Stress, Psychological ,Transcription Factors - Abstract
J. Neurochem. (2010) 113, 601–614. Abstract The critical sequence of molecular, neurotransmission and synaptic disruptions that underpin the emergence of psychiatric disorders like schizophrenia remain to be established with progress only likely using animal models that capture key features of such disorders. We have related the emergence of behavioural, neurochemical and synapse ultrastructure deficits to transcriptional dysregulation in the medial prefrontal cortex of Wistar rats reared in isolation. Isolation reared animals developed sensorimotor deficits at postnatal day 60 which persisted into adulthood. Analysis of gene expression prior to the emergence of the sensorimotor deficits revealed a significant disruption in transcriptional control, notably of immediate early and interferon-associated genes. At postnatal day 60 many gene transcripts relating particularly to GABA transmission and synapse structure, for example Gabra4, Nsf, Syn2 and Dlgh1, transiently increased expression. A subsequent decrease in genes such as Gria2 and Dlgh2 at postnatal day 80 suggested deficits in glutamatergic transmission and synapse integrity, respectively. Microdialysis studies revealed decreased extracellular glutamate suggesting a state of hypofrontality while ultrastructural analysis showed total and perforated synapse complement in layer III to be significantly reduced in the prefrontal cortex of postnatal day 80 isolated animals. These studies provide a molecular framework to understand the developmental emergence of the structural and behavioural characteristics that may in part define psychiatric illness.
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- 2010
5. Estrogen Receptor Neurobiology and its Potential for Translation into Broad Spectrum Therapeutics for CNS Disorders
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Feng Liu, Karen L. Marquis, Luis C Muñiz, Garth T. Whiteside, Robert H. Ring, Nicholas J. Brandon, Menelas N. Pangalos, and Zoë A. Hughes
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Central Nervous System ,medicine.drug_class ,Neurogenesis ,Synaptogenesis ,Pain ,Estrogen receptor ,Anxiety ,Biology ,Neurobiology ,Alzheimer Disease ,medicine ,Animals ,Estrogen Receptor beta ,Humans ,Pain Management ,Transcription factor ,Neuroinflammation ,Inflammation ,Regulation of gene expression ,Depressive Disorder ,Neurosecretion ,Estrogen Receptor alpha ,Estrogens ,General Medicine ,Gene Expression Regulation ,Estrogen ,Synaptic plasticity ,Schizophrenia ,Signal transduction ,Neuroscience ,hormones, hormone substitutes, and hormone antagonists ,Transcription Factors - Abstract
Estrogens are hormones that modulate a diverse array of effects during development and adulthood. The effects of estrogen are mediated by two estrogen receptor (ER) isotypes, ERalpha and ERbeta, which classically function as transcription factors to modulate specific target gene expression and in addition regulate a growing list of intracellular signaling cascades. These receptors share protein sequence homology and protein-motif organization but have distinct differences in their tissue distribution and binding affinities for their ligands. In the nervous system estrogen has been implicated to play a role in a number of processes which regulate synaptic plasticity including synaptogenesis and neurogenesis. The role for estrogen in a range of neurological and neuropsychiatric diseases is also becoming very apparent. Estrogen is able to regulate processes and behaviours relevant for both Alzheimer's disease and schizophrenia and to modulate neuroendocrine and inflammatory processes important in neuroinflammation, anxiety and depressive disorders as well as chronic pain. We will consider the rationale for estrogen-based therapies for diseases of the nervous system. In particular we will highlight the molecular mechanisms and signal transduction pathways most likely underlying the effects of estrogen in the CNS.
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- 2009
6. Phosphodiesterase 10A Inhibitor Activity in Preclinical Models of the Positive, Cognitive, and Negative Symptoms of Schizophrenia
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Li-Xin Jiang, Steven M. Grauer, Feng Liu, Sheree F. Logue, Nicholas J. Brandon, Barbara Langen, Michael S. Malamas, Ute Egerland, Rachel Navarra, Cody Kelley, Erik I. Charych, Thomas A. Comery, Michy P. Kelly, Karen L. Marquis, Radka Graf, Thorsten Hage, Julie A. Brennan, and Virginia L. Pulito
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Male ,Reflex, Startle ,Apomorphine ,Phosphodiesterase Inhibitors ,Pharmacology ,Rats, Sprague-Dawley ,Mice ,Glutamatergic ,Cognition ,Dopamine ,Avoidance Learning ,medicine ,Animals ,Social Behavior ,Receptor ,Prepulse inhibition ,Catalepsy ,Mice, Inbred BALB C ,Sensory gating ,Phosphoric Diester Hydrolases ,Reverse Transcriptase Polymerase Chain Reaction ,Dopaminergic ,Phosphodiesterase ,Rats ,Mice, Inbred C57BL ,Neostriatum ,medicine.anatomical_structure ,Quinolines ,Pyrazoles ,Molecular Medicine ,Schizophrenic Psychology ,PDE10A ,Dizocilpine Maleate ,Stereotyped Behavior ,Psychology ,Excitatory Amino Acid Antagonists ,Antipsychotic Agents ,medicine.drug - Abstract
Following several recent reports that suggest that dual cAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors may present a novel mechanism to treat positive symptoms of schizophrenia, we sought to extend the preclinical characterization of two such compounds, papaverine [1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline] and MP-10 [2-{[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quinoline], in a variety of in vivo and in vitro assays. Both of these compounds were active in a range of antipsychotic models, antagonizing apomorphine-induced climbing in mice, inhibiting conditioned avoidance responding in both rats and mice, and blocking N-methyl-D-aspartate antagonist-induced deficits in prepulse inhibition of acoustic startle response in rats, while improving baseline sensory gating in mice, all of which strengthen previously reported observations. These compounds also demonstrated activity in several assays intended to probe negative symptoms and cognitive deficits, two disease domains that are underserved by current treatments, with both compounds showing an ability to increase sociality in BALB/cJ mice in the social approach/social avoidance assay, enhance social odor recognition in mice and, in the case of papaverine, improve novel object recognition in rats. Biochemical characterization of these compounds has shown that PDE10A inhibitors modulate both the dopamine D1-direct and D2-indirect striatal pathways and regulate the phosphorylation status of a panel of glutamate receptor subunits in the striatum. It is striking that PDE10A inhibition increased the phosphorylation of the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor GluR1 subunit at residue serine 845 at the cell surface. Together, our results suggest that PDE10A inhibitors alleviate both dopaminergic and glutamatergic dysfunction thought to underlie schizophrenia, which may contribute to the broad-spectrum efficacy.
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- 2009
7. WAY-163909, a 5-HT2C agonist, enhances the preclinical potency of current antipsychotics
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Christine Huselton, Steven M. Grauer, Zhi Liu, Karen L. Marquis, Amy Sung, Radka Graf, Sheree F. Logue, Rachel Navarra, Thomas A. Comery, Sharon Rosenzweig-Lipson, and Gary Paul Stack
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Male ,Agonist ,Reflex, Startle ,Indoles ,Apomorphine ,medicine.drug_class ,medicine.medical_treatment ,Atypical antipsychotic ,Pharmacology ,Catalepsy ,Rats, Sprague-Dawley ,Mice ,Avoidance Learning ,Haloperidol ,medicine ,Animals ,Antipsychotic ,Clozapine ,Drug Synergism ,Azepines ,medicine.disease ,Typical antipsychotic ,Rats ,Stereotypy (non-human) ,Drug Therapy, Combination ,Dizocilpine Maleate ,Stereotyped Behavior ,Psychology ,Serotonin 5-HT2 Receptor Agonists ,Antipsychotic Agents ,medicine.drug - Abstract
5-HT(2C) agonists, by decreasing mesolimbic dopamine without affecting nigrostriatal dopamine, are predicted to have antipsychotic efficacy with low extrapyramidal side effects (EPS). Combining 5-HT(2C) agonists with low doses of existing antipsychotics could increase treatment efficacy while reducing treatment liabilities such as EPS (typical antipsychotics), and the propensity for weight gain (atypical antipsychotics).The objectives of these studies were to combine WAY-163909, a selective 5-HT(2C) agonist, with either the typical antipsychotic haloperidol, or the atypical antipsychotic clozapine, at doses that were ineffective on their own, with the expectation that a shift in potency in several rodent behavior models predictive of antipsychotic activity would occur.In mice, co-administration of either haloperidol, or clozapine, produced a significant leftward shift in the ability of WAY-163909 to block apomorphine-induced climbing behavior, without any affect on apomorphine-induced stereotypy or an increased propensity for catalepsy. In the rat-conditioned avoidance model, WAY-163909 was combined with either haloperidol or clozapine at doses that individually produced reductions in avoidance response on the order of 10%, while the combination of WAY-163909 and either of the antipsychotics resulted in a greater than 70% reduction in avoidance, with no evidence of response failures, or pharmacokinetic interaction.Doses of either haloperidol or clozapine, that failed to antagonize an MK-801 induced deficit in prepulse inhibition, significantly attenuated the sensory gating deficit when combined with WAY-163909. Data support the notion that 5-HT(2C) receptor agonists, co-administered with other marketed antipsychotics, allow for dose sparing with a more favorable side-effect profile.
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- 2008
8. ADX47273 [S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: A Novel Metabotropic Glutamate Receptor 5-Selective Positive Allosteric Modulator with Preclinical Antipsychotic-Like and Procognitive Activities
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Steven M. Grauer, Peter J. Atkinson, Michael A. Olsen, Cody Kelley, Deborah L. Smith, Margaret Lai, Guoming Zhang, Feng Liu, Sharon Rosenzweig-Lipson, Chad E. Beyer, Michael Popiolek, Adam M. Gilbert, Mark Day, Karen L. Marquis, Radka Graf, Rachel Navarra, Claudine Pulicicchio, Farhana Pruthi, Xavier Z. Khawaja, Evguenia Kouranova, Sheree F. Logue, Tom A. Comery, Caitlin Wantuch, Mark H. Pausch, and Nicholas J. Brandon
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Allosteric modulator ,Receptor, Metabotropic Glutamate 5 ,Allosteric regulation ,Drug Evaluation, Preclinical ,Prefrontal Cortex ,CDPPB ,Pharmacology ,Receptors, Metabotropic Glutamate ,Hippocampus ,Cell Line ,Cognition ,Allosteric Regulation ,Piperidines ,Dopamine ,Avoidance Learning ,medicine ,Animals ,Humans ,Phencyclidine ,Brain Chemistry ,Oxadiazoles ,Dose-Response Relationship, Drug ,Metabotropic glutamate receptor 5 ,Chemistry ,Glutamate receptor ,Rats ,Metabotropic glutamate receptor ,Molecular Medicine ,Antipsychotic Agents ,medicine.drug - Abstract
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), but not [(3)H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.
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- 2008
9. Activation of estrogen receptor-β regulates hippocampal synaptic plasticity and improves memory
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Cody Kelley, Stephen J. Moss, Daniel Bitran, Ronald F. Mervis, Rachel Navarra, Raquel Revilla-Sanchez, Amy Sung, Mark Day, Guoming Zhang, Nicholas J. Brandon, Feng Liu, Luis C Muñiz, Karen L. Marquis, Warren D. Hirst, Robert L. Arias, Menelas N. Pangalos, Steven M. Grauer, Peter H. Reinhart, and Virginia L. Pulito
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Male ,Agonist ,medicine.drug_class ,Dendritic Spines ,Ovariectomy ,Long-Term Potentiation ,Estrogen receptor ,Biology ,Hippocampal formation ,Hippocampus ,Synaptic Transmission ,Mice ,Organ Culture Techniques ,Memory ,medicine ,Animals ,Estrogen Receptor beta ,Phosphorylation ,Cyclic AMP Response Element-Binding Protein ,Maze Learning ,skin and connective tissue diseases ,Estrogen receptor beta ,Mice, Knockout ,Neurons ,Neuronal Plasticity ,Estradiol ,General Neuroscience ,Estrogens ,Long-term potentiation ,Rats ,Mice, Inbred C57BL ,body regions ,medicine.anatomical_structure ,nervous system ,Knockout mouse ,Synaptophysin ,biology.protein ,Female ,Neuron ,Neuroscience - Abstract
Estrogens have long been implicated in influencing cognitive processes, yet the molecular mechanisms underlying these effects and the roles of the estrogen receptors alpha (ERalpha) and beta (ERbeta) remain unclear. Using pharmacological, biochemical and behavioral techniques, we demonstrate that the effects of estrogen on hippocampal synaptic plasticity and memory are mediated through ERbeta. Selective ERbeta agonists increased key synaptic proteins in vivo, including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ERbeta knockout mice. In hippocampal slices, ERbeta activation enhanced long-term potentiation, an effect that was absent in slices from ERbeta knockout mice. ERbeta activation induced morphological changes in hippocampal neurons in vivo, including increased dendritic branching and increased density of mushroom-type spines. An ERbeta agonist, but not an ERalpha agonist, also improved performance in hippocampus-dependent memory tasks. Our data suggest that activation of ERbeta can regulate hippocampal synaptic plasticity and improve hippocampus-dependent cognition.
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- 2008
10. Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents
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Jessica E. Malberg, Gary Paul Stack, James E. Barrett, Sharon Rosenzweig-Lipson, John Dunlop, Annmarie Louise Sabb, Steven M. Grauer, P J Mitchell, Stacey J. Sukoff Rizzo, Julie A. Brennan, John F. Cryan, Karen L. Marquis, and Irwin Lucki
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Male ,Agonist ,Obsessive-Compulsive Disorder ,medicine.medical_specialty ,Indoles ,medicine.drug_class ,Drinking Behavior ,Rats, Inbred WKY ,Rats, Sprague-Dawley ,Sexual Behavior, Animal ,chemistry.chemical_compound ,Internal medicine ,Receptor, Serotonin, 5-HT2C ,medicine ,Animals ,Rats, Long-Evans ,Rats, Wistar ,Swimming ,Pharmacology ,SB-206553 ,Dose-Response Relationship, Drug ,Depression ,business.industry ,Azepines ,Receptor antagonist ,Antidepressive Agents ,Rats ,Serotonin Receptor Agonists ,Aggression ,Disease Models, Animal ,Sexual Dysfunction, Physiological ,Endocrinology ,chemistry ,Antidepressant ,Female ,5-HT2C receptor agonist ,SB-242084 ,business ,Endogenous agonist ,Behavioural despair test - Abstract
Activation of one or more of the serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of SSRIs. The present studies were conducted to evaluate the effects of the novel 5-HT2C receptor agonist WAY-163909 in animal models of antidepressant activity (forced swim test (FST), resident–intruder, olfactory bulbectomy (BULB)), in a schedule-induced polydipsia (SIP) model of obsessive–compulsive disorder and in a model for evaluating sexual dysfunction. WAY-163909 (10 mg/kg, i.p. or s.c.) decreased immobility time in Wistar–Kyoto rats in the FST, effects that were reversed by the 5-HT2C/2B receptor antagonist SB 206553. Moreover, in Sprague-Dawley rats, the profile of WAY-163909 (decreased immobility, increased swimming) in the FST was comparable to the effects of SSRIs. Acute treatment with WAY-163909 (0.33 mg/kg, s.c.) decreased rodent aggression at doses lower than those required for decreasing total behavior. Administration of WAY-163909 (3 mg/kg, i.p.) for 5 or 21 days decreased the BULB-induced hyperactivity in rats. Additionally, acute administration of WAY-163909 (3 mg/kg, i.p.) decreased adjunctive drinking in a SIP model. The effects of WAY-163909 were reversed by the 5-HT2C/2B receptor antagonist SB 206553 and the selective 5-HT2C receptor antagonist SB 242084. Chronic administration of WAY-163909 produced deficits in sexual function at doses higher (10 mg/kg, i.p.) than those required for antidepressant-like effects in the BULB model. Taken together, these results demonstrate that the novel 5-HT2C receptor agonist WAY-163909 produces rapid onset antidepressant-like effects in animal models and may be a novel treatment for depression.
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- 2007
11. Glutamate transport inhibitors as targets for treating psychosis
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Karen L. Marquis and John Dunlop
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Pharmacology ,Psychosis ,Metabotropic glutamate receptor 7 ,Glutamate receptor ,Biology ,medicine.disease ,Synapse ,Dopamine ,Drug Discovery ,medicine ,Molecular Medicine ,NMDA receptor ,Metabotropic glutamate receptor 3 ,Metabotropic glutamate receptor 2 ,medicine.drug - Abstract
Agents targeting the dopamine system have been the mainstay of antipsychotic drug therapy for decades. Recent attention has focused on the role of glutamate in schizophrenia and many components of the glutamate synapse represent evolving molecular targets. Among the proteins regulating glutamate availability in the synapse, the excitatory amino acid transporters (EAATs) and in particular EAAT3, a neuronal subtype expressed throughout the central nervous system, might offer an approach to manipulating the glutamate synapse as a strategy for antipsychotic drug development.
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- 2006
12. WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-Octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A Novel 5-Hydroxytryptamine 2C Receptor-Selective Agonist with Preclinical Antipsychotic-Like Activity
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Annmarie Louise Sabb, Karen L. Marquis, James E. Barrett, Boyd L. Harrison, Sharon Rosenzweig-Lipson, Lee A. Dawson, Michael J. Piesla, Gary Paul Stack, Julie A. Brennan, Sheree F. Logue, Herbert Y. Meltzer, Huy Nguyen, Tom A. Comery, Steven M. Grauer, and Charles R. Ashby
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Male ,Agonist ,Reflex, Startle ,Indoles ,Apomorphine ,medicine.drug_class ,Microdialysis ,Striatum ,Motor Activity ,Catalepsy ,Pharmacology ,Nucleus accumbens ,Rats, Sprague-Dawley ,Mice ,Dopamine ,Avoidance Learning ,medicine ,Animals ,Amphetamine ,Chemistry ,Ventral Tegmental Area ,Azepines ,medicine.disease ,Receptor antagonist ,Rats ,Serotonin Receptor Agonists ,Substantia Nigra ,Ventral tegmental area ,medicine.anatomical_structure ,Mice, Inbred DBA ,Molecular Medicine ,Dizocilpine Maleate ,Stereotyped Behavior ,Serotonin 5-HT2 Receptor Agonists ,Antipsychotic Agents ,medicine.drug - Abstract
Serotonin-2C (5-HT 2C ) receptor antagonists and agonists have been shown to affect dopamine (DA) neurotransmission, with agonists selectively decreasing mesolimbic DA. As antipsychotic efficacy is proposed to be associated with decreased mesolimbic DA neurotransmission by virtue of DA D 2 receptor antagonism, the 5-HT 2C -selective receptor agonist, WAY-163909 [(7 bR ,10 aR )-1,2, 3,4,8,9,10,10 a -octahydro-7 bH -cyclopenta-[ b ][1,4]diazepino[6,7, 1hi]indole], was evaluated in animal models of schizophrenia and in vivo microdialysis and electrophysiology to determine the effects on mesolimbic and nigrostriatal DA neurotransmission. Similar to clozapine, WAY-163909 (1.7–30 mg/kg i.p.) decreased apomorphine-induced climbing with little effect on stereotypy and no significant induction of catalepsy. WAY-163909 (0.3–3 mg/kg s.c.) more potently reduced phencyclidine-induced locomotor activity compared with d -amphetamine with no effect on spontaneous activity. WAY-163909 (1.7–17 mg/kg i.p.) reversed MK-801 (5 H -dibenzo[ a , d ]cyclohepten-5,10-imine (dizocilpine maleate)- and DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-disrupted prepulse inhibition of startle (PPI) and improved PPI in DBA/2N mice. In conditioned avoidance responding, WAY-163909 (0.3–3 mg/kg i.p.; 1–17 mg/kg p.o.) reduced avoidance responding, an effect blocked by the 5-HT 2B/2C receptor antagonist SB 206553 [5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3- f ]indole]. WAY-163909 (10 mg/kg s.c.) selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum. Likewise, in vivo electrophysiological recordings showed a decrease in the number of spontaneously firing DA neurons in the ventral tegmental area but not in the substantia nigra with both acute and chronic (21-day) administration of WAY-163909 (1–10 mg/kg i.p.). Thus, the profile of the 5-HT 2C selective receptor agonist WAY-163909 is similar to that of an atypical antipsychotic and additionally may have rapid onset properties.
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- 2006
13. Pharmacological Profile of the 5-HT2CReceptor Agonist WAY-163909; Therapeutic Potential in Multiple Indications
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Louis Leung, Sharon Rosenzweig-Lipson, Cynthia Cheesman, Heng-Keang Lim, John Dunlop, John Kao, and Karen L. Marquis
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Pharmacology ,Agonist ,Indoles ,medicine.drug_class ,Drug discovery ,Reviews ,Azepines ,medicine.disease ,Antidepressive Agents ,Eating ,Neuropsychology and Physiological Psychology ,Erectile dysfunction ,Migraine ,Schizophrenia ,medicine ,Animals ,Humans ,Anxiety ,medicine.symptom ,Receptor ,Psychology ,Serotonin 5-HT2 Receptor Agonists ,5-HT receptor ,Antipsychotic Agents - Abstract
The 5‐HT(2C) receptor subtype has been implicated in a wide variety of conditions including obesity, anxiety, depression, obsessive compulsive disorder, schizophrenia, migraine and erectile dysfunction and as a consequence has received considerable attention as a target for drug discovery. Here we review the pharmacological, pharmacokinetic and toxicological profile of WAY‐163909 {(7bR,10aR)‐1,2,3,4,8,9,10,10a‐octahydro‐7bH‐cyclopenta‐[b][1,4]diazepino[6,7,1hi]indole}, a novel 5‐HT(2C) receptor selective agonist. Consistent with a potential therapeutic utility in obesity, schizophrenia and depression WAY‐163909 was found to have robust dose‐dependent effects in animal models of obesity, psychotic‐like behavior or depression.
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- 2006
14. The effect of mGlu5 receptor positive allosteric modulators on signaling molecules in brain slices
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Adam M. Gilbert, Kaapjoo Park, Karen L. Marquis, Guoming Zhang, Geoffrey Hornby, Dmytro Vasylyovych Vasylyev, Mark R. Bowlby, Feng Liu, and Terrance H. Andree
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Male ,Allosteric modulator ,Receptor, Metabotropic Glutamate 5 ,Allosteric regulation ,Glycine ,Action Potentials ,Phthalimides ,In Vitro Techniques ,Biology ,Receptors, Metabotropic Glutamate ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,Mice ,Enzyme-linked receptor ,Animals ,Phosphorylation ,Cyclic AMP Response Element-Binding Protein ,Extracellular Signal-Regulated MAP Kinases ,Cells, Cultured ,Pharmacology ,Dose-Response Relationship, Drug ,Metabotropic glutamate receptor 5 ,Pyramidal Cells ,Brain ,Drug Synergism ,Resorcinols ,Cell biology ,Mice, Inbred C57BL ,Biochemistry ,Metabotropic glutamate receptor ,Benzamides ,Metabotropic glutamate receptor 1 ,NMDA receptor ,Rabbits ,Metabotropic glutamate receptor 2 ,Excitatory Amino Acid Antagonists ,Signal Transduction - Abstract
Positive allosteric modulators of metabotropic glutamate receptor subtype 5 (mGlu5) have promising therapeutic potential. The effects of selective mGlu5 receptor positive allosteric modulators on signaling molecules in brain slices have not been previously reported. The current study demonstrated that the selective mGlu5 receptor positive allosteric modulator, N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2yl)-methyl]phenyl}-2-hydrobenzamide (CPPHA) potentiated the response to a subthreshold concentration of 3,5-dihydroxy-phenylglycine (DHPG) on extracellular signal-regulated protein kinase (ERK) and cyclic-AMP responsive element-binding protein (CREB) activity, as well as N-methyl d-aspartate (NMDA) receptor subunit NR1 phosphorylation in cortical and hippocampal slices. These results suggest that allosteric modulators of mGlu5 receptor could have physiologically significant effects by potentiating the actions of glutamate.
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- 2006
15. The inhibition of glycogen synthase kinase 3β by a metabotropic glutamate receptor 5 mediated pathway confers neuroprotection to Aβ peptides
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Karen L. Marquis, Peter H. Reinhart, Terrance H. Andree, Guoming Zhang, Xiaohai Gong, and Feng Liu
- Subjects
medicine.medical_specialty ,Metabotropic glutamate receptor 5 ,macromolecular substances ,Biology ,Biochemistry ,Neuroprotection ,Cell biology ,Wortmannin ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Endocrinology ,chemistry ,GSK-3 ,Metabotropic glutamate receptor ,Internal medicine ,medicine ,GSK3B ,Protein kinase B ,PI3K/AKT/mTOR pathway - Abstract
Activation of glycogen synthase kinase 3beta (Gsk3beta) has been shown to be a key component in signaling pathways that underlie neurodegeneration and neurodegenerative disease. Conversely, inactivation of Gsk3beta by phosphoinositide 3-kinase (PI3K)/Akt is an important neuroprotective mechanism. Previous studies have shown that agonist activation of group I metabotropic glutamate receptors (mGluRs) can increase neuronal survival and prevent apoptosis. However, little is known about the signaling pathways that couple mGluR5 to neuroprotection. In this report, we investigated whether activation of the PI3K/Akt/Gsk3beta pathway, which has been shown to have an important neuroprotective mechanism, is required for mGluR5 activation mediated neuroprotection against beta-amyloid. We found that brief incubations of mouse hippocampal slices with (R,S)-3,5-dihydroxyphenylglycine (DHPG) resulted in increased phosphorylation of Akt and Gsk3beta. The PI3K inhibitors, LY294002 and wortmannin, blocked the DHPG-induced increased phosphorylation of Akt and Gsk3beta. Similar results were observed in rat primary hippocampal cultures. Finally, we found that the PI3K inhibitor LY294002 can block (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) mediated neuroprotection against beta-amyloid. Thus, these findings suggest that mGluR5 can modulate the PI3K/Akt/Gsk3beta pathway in the hippocampus, and that modulation of this signaling pathway can reverse beta-amyloid-induced neuronal toxicity.
- Published
- 2005
16. Acute γ-Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's Disease
- Author
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Karen L. Marquis, Suzan Aschmies, Hua Zhou, Robert Martone, Kevin Atchison, June Sonnenberg-Reines, Anthony Kreft, Menelas N. Pangalos, Thomas A. Comery, J. Steven Jacobsen, George Diamantidis, and Xiaohai Gong
- Subjects
Genetically modified mouse ,Aging ,medicine.medical_specialty ,Amyloid ,Phosphodiesterase Inhibitors ,Transgene ,Mice, Transgenic ,Amyloid beta-Protein Precursor ,Mice ,Cognition ,Alzheimer Disease ,Internal medicine ,Conditioning, Psychological ,Endopeptidases ,medicine ,Amyloid precursor protein ,Animals ,Aspartic Acid Endopeptidases ,Dementia ,Enzyme Inhibitors ,Pathological ,Triglycerides ,gamma-Aminobutyric Acid ,Rolipram ,Amyloid beta-Peptides ,biology ,General Neuroscience ,Fear ,medicine.disease ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Disease Models, Animal ,Endocrinology ,3',5'-Cyclic-AMP Phosphodiesterases ,Mutation ,biology.protein ,Amyloid Precursor Protein Secretases ,Brief Communications ,Cognition Disorders ,Psychology ,Neuroscience ,Amyloid precursor protein secretase ,medicine.drug - Abstract
Transgenic mice (Tg2576) overexpressing the Swedish mutation of the human amyloid precursor protein display biochemical, pathological, and behavioral markers consistent with many aspects of Alzheimer's disease, including impaired hippocampal function. Impaired, hippocampal-dependent, contextual fear conditioning (CFC) is observed in mice as young as 20 weeks of age. This impairment can be attenuated after treatment before training with the phosphodiesterase-4 inhibitor rolipram (0.1 mg/kg, i.p.). A rolipram-associated improvement is also observed in the littermate controls, suggesting that the effect of rolipram is independent of β-amyloid. Acute treatment before training (but not after training or before testing) with the γ-secretase inhibitor (GSI)N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine-t-butylester (DAPT), at a dose that reduces brain concentrations of β-amyloid (100 mg/kg), attenuates the impairment in 20- to 65-week-old Tg2576 mice. Importantly, DAPT had no effect on performance of control littermates. These data are supportive of a role of β-amyloid in the impairment of CFC in Tg2576 mice. Furthermore, they suggest that acute treatment with GSI may provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease.
- Published
- 2005
17. Lecozotan (SRA-333): A Selective Serotonin 1A Receptor Antagonist That Enhances the Stimulated Release of Glutamate and Acetylcholine in the Hippocampus and Possesses Cognitive-Enhancing Properties
- Author
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Jerrry J. Buccafusco, Deborah L. Smith, Josie Harder, Stacey J. Sukoff, Lee A. Dawson, Magid Abou-Gharbia, Michael J. Piesla, Sharon Rosenzweig-Lipson, Pedro Rada, Deborah Jones, Terry Andree, Michael G. Kelly, Wayne E. Childers, Bart Hoebel, Matthew Womack, Barrett James Edward, Stanley Nawoschik, Lee E. Schechter, Karen L. Marquis, and Alvin V. Terry
- Subjects
Male ,Agonist ,Methoxydimethyltryptamines ,medicine.drug_class ,Microdialysis ,Glutamic Acid ,Hippocampus ,Serotonin 5-HT1 Receptor Antagonists ,Pharmacology ,Piperazines ,Dioxanes ,Discrimination Learning ,Rats, Sprague-Dawley ,Cognition ,Alzheimer Disease ,Ganglia, Spinal ,medicine ,Animals ,Columbidae ,Saimiri ,8-Hydroxy-2-(di-n-propylamino)tetralin ,Chemistry ,Antagonist ,Callithrix ,Receptor antagonist ,Macaca mulatta ,Acetylcholine ,Rats ,Lecozotan ,Mechanism of action ,Molecular Medicine ,5-HT1A receptor ,Cholinergic ,Female ,Serotonin Antagonists ,medicine.symptom ,medicine.drug - Abstract
Recent data has suggested that the 5-hydroxytryptamine (5-HT)(1A) receptor is involved in cognitive processing. A novel 5-HT(1A) receptor antagonist, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacological assays as a drug to treat cognitive dysfunction, is reported. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT(1A) receptor antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg s.c.) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg s.c.) of 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus. Chronic administration of lecozotan did not induce 5-HT(1A) receptor tolerance or desensitization in a behavioral model indicative of 5-HT(1A) receptor function. In drug discrimination studies, lecozotan (0.01-1 mg/kg i.m.) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT(1A) agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg p.o.). Learning deficits induced by the glutamatergic antagonist MK-801 [(-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] (assessed by perceptually complex and visual spatial discrimination) and by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination) were reversed by lecozotan (2 mg/kg i.m.) in marmosets. The heterosynaptic nature of the effects of lecozotan imbues this compound with a novel mechanism of action directed at the biochemical pathologies underlying cognitive loss in Alzheimer's disease.
- Published
- 2005
18. New Generation Dopaminergic Agents. Part 8: Heterocyclic Bioisosteres that Exploit the 7-OH-2-(aminomethyl)chroman D2 Template
- Author
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Richard Eric Mewshaw, Rulin Zhao, Terrance H. Andree, Hossein Mazandarani, Joseph Coupet, Xiaojie Shi, Julie A. Brennan, and Karen L. Marquis
- Subjects
Receptors, Dopamine D2 ,Chemistry ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Dopaminergic ,Pharmaceutical Science ,Templates, Genetic ,Biochemistry ,Chemical synthesis ,Models, Structural ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dopamine Agonists ,Drug Discovery ,Molecular Medicine ,Benzopyrans ,Enantiomer ,Molecular Biology ,Derivative (chemistry) - Abstract
Based on the 7-OH-2-(aminomethyl)chroman dopamine D 2 template ( 2 ) is described the preparation and resolution of two bioisosteric analogues. The benzimidazol-2-one derivative ( 6 ) had similar affinity to the known indolone derivative ( 4 ).
- Published
- 2002
19. Intracerebral administration of metabotropic glutamate receptor agonists disrupts prepulse inhibition of acoustic startle in Sprague-Dawley rats
- Author
-
Steven M. Grauer and Karen L. Marquis
- Subjects
Male ,Agonist ,Reflex, Startle ,medicine.drug_class ,Dopamine ,Glutamine ,Striatum ,Pharmacology ,Nucleus accumbens ,Receptors, Metabotropic Glutamate ,Nucleus Accumbens ,Rats, Sprague-Dawley ,Excitatory Amino Acid Agonists ,medicine ,Animals ,Cycloleucine ,Prepulse inhibition ,Visual Cortex ,Chemistry ,Glutamate receptor ,Amino Acids, Dicarboxylic ,Rats ,Inhibition, Psychological ,Neuroprotective Agents ,Metabotropic receptor ,Acoustic Stimulation ,Metabotropic glutamate receptor ,Neuroscience ,medicine.drug - Abstract
The functional role of striatal metabotropic glutamate receptors (mGluRs) was examined by measuring prepulse inhibition (PPI) of an acoustic startle response following the intracerebral administration of selective agonists in male Sprague-Dawley rats prepared with bilateral cannulae aimed at either the nucleus accumbens or dorsal striatum. mGluR subtypes (1-8) are classed in three groups based on sequence homology, signal transduction mechanism and pharmacology. Intra-accumbens IS,3R-ACPD, an agonist at group 1 and 2 mGluRs (0.5-1.0 micromol/2 microl), caused a dose-dependent loss of PPI. The effect of 1S,3R-ACPD was diminished when injected into dorsal striatum. Intra-accumbens infusion of the group 1 selective agonist 3,5-DHPG (1 micromol) and the group 2 selective agonist L-CCG-I (100 nmol) also led to statistically significant disruptions of PPI, while the group 3 selective agonist L-AP4 (0.4-1.0 micromol) had no significant effect. Although the group 1/2 mGluR antagonist (+) MCPG (0.5 micromol) had no significant effect of its own on PPI, co-administration with IS,3R-ACPD (1 micromol) blocked ACPD-induced loss of PPI. In addition, pretreatment (30 min) with haloperidol (0.3 mg/kg IP) attenuated the PPI disruption induced by 1 micromol 1S,3R-ACPD, suggesting dopamine may play a role in mGluR agonist induced loss of PPI. These results support a role for group 1 and group 2 mGluRs in the nucleus accumbens in the regulation of PPI, a measure of sensory gating. As PPI is abnormal in some patient populations, such as Huntington's and schizophrenia, mGluRs may have potential as novel therapeutic targets for these diseases.
- Published
- 1999
20. New generation dopaminergic agents. 5. heterocyclic bioisosteres that exploit the 3-OH-N1-phenylpiperazine dopaminergic template
- Author
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Karen L. Marquis, Terrance H. Andree, Georgia B. McGaughey, Antoine Verwijs, James Albert Nelson, Joseph Coupet, Julie A. Brennan, Richard Eric Mewshaw, Xiaojie Shi, and Hossein Mazandarani
- Subjects
Agonist ,Indoles ,Molecular model ,medicine.drug_class ,Stereochemistry ,Dopamine Agents ,Clinical Biochemistry ,Pharmaceutical Science ,Phenylpiperazine ,Biochemistry ,Chemical synthesis ,Piperazines ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dopamine receptor D2 ,Drug Discovery ,medicine ,Animals ,Molecular Biology ,Psychotropic Drugs ,Bicyclic molecule ,Receptors, Dopamine D2 ,Chemistry ,Organic Chemistry ,Dopaminergic ,Receptors, Dopamine D3 ,Templates, Genetic ,Ligand (biochemistry) ,Corpus Striatum ,Rats ,Kinetics ,Dopamine Agonists ,Molecular Medicine ,Benzimidazoles - Abstract
The synthesis of several bioisosteric analogs based on the 3-OH-N1-phenylpiperazine dopamine D2 agonist template (i.e., 4) is described. The indolone (5) and 2-CF3-benzimidazole (13) were observed to have excellent affinity for the D2 receptor. Several D4 selective compounds were also identified. Molecular modeling studies and a putative bioactive conformation are discussed.
- Published
- 1998
21. New generation dopaminergic agents 4. Exploiting the 2-methyl chroman scaffold. Synthesis and evaluation of two novel series of 2-(aminomethyl)-3,4,7,9-tetrahydro-2H-pyrano[2,3-e]indole and indol-8-one derivatives
- Author
-
Michael Byron Webb, Taylor Spangler, Magid Abou-Gharbia, Karen L. Marquis, Hossein Mazandarani, Georgia B. McGaughey, Julie A. Brennan, Theodore Wasik, Joseph Coupet, Rosemary Scerni, Terrance H. Andree, Gary Paul Stack, Richard Eric Mewshaw, and Xiaojie Shi
- Subjects
Agonist ,Indole test ,Scaffold ,Intrinsic activity ,medicine.drug_class ,Chemistry ,Stereochemistry ,Organic Chemistry ,Dopaminergic ,Rational design ,Biochemistry ,Combinatorial chemistry ,Drug Discovery ,medicine - Abstract
The rational design, synthesis, and evaluation of two novel series of 2-(aminomethyl)-3,4,7,9-tetrahydro-2H-pyrano[2,3-e]indole and indolone derivatives are disclosed, based on the recently discovered D 2 agonist phenolic template prototype [i.e. the 7-OH-2-(aminomethyl)chroman nucleus]. The indolones were observed to have higher affinity and intrinsic activity than the corresponding indoles.
- Published
- 1998
22. 5-HT(2C) agonists as therapeutics for the treatment of schizophrenia
- Author
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Sharon, Rosenzweig-Lipson, Thomas A, Comery, Karen L, Marquis, Jonathan, Gross, and John, Dunlop
- Subjects
Translational Research, Biomedical ,Schizophrenia ,Humans ,RNA Editing ,Heterocyclic Compounds, 4 or More Rings ,Serotonin 5-HT2 Receptor Agonists - Abstract
The 5-HT(2C) receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT(2C) receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT(2C) receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the studies suggesting the utility of either agonists or antagonists in the treatment of schizophrenia. While several 5-HT(2C) agonists have demonstrated clinical efficacy in obesity (lorcaserin, PRX-000933), the focus of this review is on the therapeutic potential of 5-HT(2C) agonists in schizophrenia. To this end, the preclinical profile of 5-HT(2C) agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy without extrapyramidal symptoms or weight gain. Recently, the selective 5-HT(2C) agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients without weight gain and with low EPS liability. These data are highly encouraging and suggest that 5-HT(2C) agonists are potential therapeutics for the treatment of psychiatric disorders.
- Published
- 2012
23. Novel triazines as potent and selective phosphodiesterase 10A inhibitors
- Author
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Menelas N. Pangalos, James Joseph Erdei, Rudolf Schindler, Thorsten Hage, Christian Grunwald, Hans Stange, Michael S. Malamas, Julie A. Brennan, Barbara Langen, Nicholas J. Brandon, Norbert Hoefgen, Kristi Fan, Yike Ni, Boyd L. Harrison, Albert J. Robichaud, Karen L. Marquis, Radka Graf, Kevin Parris, Hans-Joachim Lankau, Steven M. Grauer, Rachel Navarra, Ute Egerland, and Thomas Kronbach
- Subjects
Drug ,Models, Molecular ,Phosphodiesterase Inhibitors ,media_common.quotation_subject ,Clinical Biochemistry ,Pharmaceutical Science ,Administration, Oral ,Pharmacology ,Hyperkinesis ,Crystallography, X-Ray ,Biochemistry ,Structure-Activity Relationship ,Pharmacokinetics ,Drug Discovery ,Potency ,Animals ,Humans ,Molecular Biology ,media_common ,ADME ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Phosphoric Diester Hydrolases ,Triazines ,Organic Chemistry ,Phosphodiesterase ,Bioavailability ,Rats ,Molecular Medicine ,PDE10A ,Dizocilpine Maleate ,Selectivity - Abstract
The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t1/2, bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC50 = 1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED = 0.1 mg/kg) and conditioned avoidance responding (CAR; ID50 = 0.2 mg/kg).
- Published
- 2012
24. 5-HT2C Agonists as Therapeutics for the Treatment of Schizophrenia
- Author
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Sharon Rosenzweig-Lipson, Jonathan Laird Gross, John Dunlop, Thomas A. Comery, and Karen L. Marquis
- Subjects
Agonist ,business.industry ,medicine.drug_class ,Vabicaserin ,Pharmacology ,medicine.disease ,Lorcaserin ,Neurochemical ,Extrapyramidal symptoms ,Schizophrenia ,Medicine ,Signal transduction ,medicine.symptom ,business ,Receptor ,medicine.drug - Abstract
The 5-HT2C receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT2C receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT2C receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the studies suggesting the utility of either agonists or antagonists in the treatment of schizophrenia. While several 5-HT2C agonists have demonstrated clinical efficacy in obesity (lorcaserin, PRX-000933), the focus of this review is on the therapeutic potential of 5-HT2C agonists in schizophrenia. To this end, the preclinical profile of 5-HT2C agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy without extrapyramidal symptoms or weight gain. Recently, the selective 5-HT2C agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients without weight gain and with low EPS liability. These data are highly encouraging and suggest that 5-HT2C agonists are potential therapeutics for the treatment of psychiatric disorders.
- Published
- 2012
25. Preclinical assessment of an adjunctive treatment approach for cognitive impairment associated with schizophrenia using the alpha7 nicotinic acetylcholine receptor agonist WYE-103914/SEN34625
- Author
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Flora Jow, Renza Roncarati, Thomas A. Comery, Karen L. Marquis, Steven M. Grauer, Georg C. Terstappen, Claudine Pulicicchio, Carla Scali, Simon N. Haydar, Chiara Ghiron, John Dunlop, Julie A. Brennan, Rachel L. Navarra, and Cody Kelley
- Subjects
Agonist ,Male ,alpha7 Nicotinic Acetylcholine Receptor ,medicine.drug_class ,Pyridines ,medicine.medical_treatment ,Drug Evaluation, Preclinical ,Atypical antipsychotic ,Pharmacology ,Receptors, Nicotinic ,Rats, Sprague-Dawley ,Mice ,Memory ,medicine ,Avoidance Learning ,Animals ,Urea ,Drug Interactions ,Rats, Long-Evans ,Antipsychotic ,Risperidone ,business.industry ,medicine.disease ,Rats ,Nicotinic agonist ,Schizophrenia ,Adjunctive treatment ,Drug Therapy, Combination ,business ,Cognition Disorders ,Acetylcholine ,medicine.drug ,Antipsychotic Agents - Abstract
α7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored. We determined if the memory-enhancing effects of the selective α7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914. Using the rat novel object recognition (NOR) paradigm, the maintenance of memory-enhancing activity of the α7 nAChR agonist WYE-103914 in the presence of risperidone was examined. Similarly, in the standard tests of antipsychotic-like activity, apomorphine-induced climbing (AIC) in mice and conditioned avoidance responding (CAR) in rats, the preservation of antipsychotic-like activity of risperidone was evaluated in the presence of WYE-103914. WYE-103914 exhibited memory-enhancing activity in rat NOR, and this effect of WYE-103914 was retained in the presence of risperidone. In AIC, the atypical antipsychotic profile of risperidone was not significantly altered by WYE-103914. In contrast, WYE-103914 moderately potentiated the efficacy profile of risperidone in CAR, an effect that did not appear to be convincingly linked to a pharmacokinetic interaction. These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with α7 nAChR agonists to address the cognitive deficits associated with schizophrenia.
- Published
- 2011
26. ChemInform Abstract: New Generation Dopaminergic Agents. Part 5. Heterocyclic Bioisosteres That Exploit the 3-OH-N1-Phenylpiperazine Dopaminergic Template
- Author
-
Terrance H. Andree, Richard Eric Mewshaw, Xiaojie Shi, H. Mazandarani, A. Verwijs, Karen L. Marquis, Georgia B. McGaughey, Julie A. Brennan, James Albert Nelson, and Joseph Coupet
- Subjects
chemistry.chemical_compound ,Chemistry ,Dopaminergic ,Phenylpiperazine ,General Medicine ,Neuroscience - Published
- 2010
27. ChemInform Abstract: New Generation Dopaminergic Agents. Part 7. Heterocyclic Bioisosteres that Exploit the 3-OH-Phenoxyethylamine D2 Template
- Author
-
Uresh Shantilal Shah, James Albert Nelson, Hossein Mazandarani, Karen L. Marquis, Joseph Coupet, Richard Eric Mewshaw, Xiaojie Shi, Julie A. Brennan, and Terrance H. Andree
- Subjects
Exploit ,Chemistry ,Dopaminergic ,General Medicine ,Combinatorial chemistry - Published
- 2010
28. Novel alpha-7 nicotinic acetylcholine receptor agonists containing a urea moiety: identification and characterization of the potent, selective, and orally efficacious agonist 1-[6-(4-fluorophenyl)pyridin-3-yl]-3-(4-piperidin-1-ylbutyl) urea (SEN34625/WYE-103914)
- Author
-
Dianne Kowal, Ugo Zanelli, Riccardo Zanaletti, Laura Maccari, Maurizio Varrone, Albert J. Robichaud, Tim Lock, Michela Valacchi, Renza Roncarati, Carla Scali, Li Di, Georg C. Terstappen, Iolanda Micco, Flora Jow, Cristiana Castaldo, Arianna Nencini, Angela Kramer, Thomas A. Comery, John Dunlop, Suzan Aschmies, Hendrick Bothmann, Karen L. Marquis, Elisa Turlizzi, Chiara Ghiron, Giuseppe Cocconcelli, Salvatore La Rosa, Simon Haydar, Boyd L. Harrison, Joanna Quinn, and Steven M. Grauer
- Subjects
Agonist ,Male ,Models, Molecular ,alpha7 Nicotinic Acetylcholine Receptor ,medicine.drug_class ,Protein Conformation ,Pyridines ,Administration, Oral ,Pharmacology ,Receptors, Nicotinic ,Substrate Specificity ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,medicine ,Structure–activity relationship ,Moiety ,Animals ,Humans ,Urea ,Nicotinic Agonists ,Receptor ,Chemistry ,Small molecule ,Rats ,Nicotinic acetylcholine receptor ,Nicotinic agonist ,Biochemistry ,Molecular Medicine - Abstract
Alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the alpha7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the alpha7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.
- Published
- 2010
29. Potent dihydroquinolinone dopamine D2 partial agonist/serotonin reuptake inhibitors for the treatment of schizophrenia
- Author
-
Jean Zhang, Ping Zhou, Tikva Carrick, Albert J. Robichaud, Rolf Feenstra, Jan-Hendrik Reinders, Dianne Kowal, Chris G. Kruse, Martina A.W. van der Neut, Yinfa Yan, David P. Rotella, Mark H. Pausch, Margaret Lai, and Karen L. Marquis
- Subjects
Serotonin reuptake inhibitor ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Quinolones ,Biochemistry ,Partial agonist ,Reuptake ,Structure-Activity Relationship ,Dopamine receptor D2 ,Drug Discovery ,Moiety ,Animals ,Molecular Biology ,biology ,Chemistry ,Receptors, Dopamine D2 ,Organic Chemistry ,Disease Models, Animal ,Norepinephrine transporter ,Dopamine Agonists ,Receptor, Serotonin, 5-HT1A ,biology.protein ,Schizophrenia ,Molecular Medicine ,Pharmacophore ,Endogenous agonist ,Selective Serotonin Reuptake Inhibitors ,Antipsychotic Agents - Abstract
A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D2 ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D2 partial agonists and serotonin reuptake inhibitors. Structure–activity studies revealed that the linker plays a key role in contributing to D2 affinity, function, and SRI activity.
- Published
- 2010
30. WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one]: a novel dopamine D2 receptor partial agonist/serotonin reuptake inhibitor with preclinical antipsychotic-like and antidepressant-like activity
- Author
-
Sharon Rosenzweig-Lipson, Deborah L. Smith, Feenstra Roelof W, Steven M. Grauer, Pierre Broqua, Rachel Navarra, David P. Rotella, Mark H. Pausch, Karen L. Marquis, Radka Graf, Albert J. Robichaud, Martina Van De Neut, Qian Lin, Claudine Pulicicchio, Farhana Pruthi, Wouter Goutier, Chad E. Beyer, Caitlin Wantuch, Julie A. Brennan, Zoë A. Hughes, Andrew C. McCreary, Margaret Lai, and Chris G. Kruse
- Subjects
Male ,Serotonin ,medicine.medical_treatment ,Serotonin reuptake inhibitor ,Dopamine ,Microdialysis ,Drug Evaluation, Preclinical ,Mice, Inbred Strains ,CHO Cells ,Pharmacology ,Motor Activity ,Serotonin 5-HT1 Receptor Antagonists ,Transfection ,Partial agonist ,Rats, Sprague-Dawley ,Mice ,Cricetulus ,Dopamine receptor D2 ,Cricetinae ,medicine ,Serotonin 5-HT2 Receptor Antagonists ,Avoidance Learning ,Animals ,Humans ,Rats, Wistar ,Antipsychotic ,Serotonin transporter ,Benzoxazoles ,biology ,Behavior, Animal ,Chemistry ,Receptors, Dopamine D2 ,Brain ,Antidepressive Agents ,Rats ,Indenes ,Dopamine Agonists ,biology.protein ,Molecular Medicine ,Aripiprazole ,Selective Serotonin Reuptake Inhibitors ,medicine.drug ,Antipsychotic Agents ,Protein Binding - Abstract
The preclinical characterization of WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one] is described. In vitro binding and functional studies revealed highest affinity to the D(2) receptor (D(2L) K(i), 4.0 nM) and serotonin transporter (K(i), 7.1 nM), potent D(2) partial agonist activity (EC(50), 0.38 nM; E(max), 30%), and complete block of the serotonin transporter (IC(50), 56.4 nM). Consistent with this in vitro profile, WS-50030 (10 mg/kg/day, 21 days) significantly increased extracellular 5-HT in the rat medial prefrontal cortex, short-term WS-50030 treatment blocked apomorphine-induced climbing (ID(50), 0.51 mg/kg) in a dose range that produced minimal catalepsy in mice and induced low levels of contralateral rotation in rats with unilateral substantia nigra 6-hydroxydopamine lesions (10 mg/kg i.p.), a behavioral profile similar to that of the D(2) partial agonist aripiprazole. In a rat model predictive of antipsychotic-like activity, WS-50030 and aripiprazole reduced conditioned avoidance responding by 42 and 55% at 10 mg/kg, respectively. Despite aripiprazole's reported lack of effect on serotonin transporters, long-term treatment with aripiprazole or WS-50030 reversed olfactory bulbectomy-induced hyperactivity at doses that did not reduce activity in sham-operated rats, indicating antidepressant-like activity for both compounds. Despite possessing serotonin reuptake inhibitory activity in addition to D(2) receptor partial agonism, WS-50030 displays activity in preclinical models predictive of antipsychotic- and antidepressant efficacy similar to aripiprazole, suggesting potential efficacy of WS-50030 versus positive and negative symptoms of schizophrenia, comorbid mood symptoms, bipolar disorder, major depressive disorder, and treatment-resistant depression. Furthermore, WS-50030 provides a tool to further explore how combining these mechanisms might differentiate from other antipsychotics or antidepressants.
- Published
- 2009
31. Tetrahydrocarbazole-based serotonin reuptake inhibitor/dopamine D2 partial agonists for the potential treatment of schizophrenia
- Author
-
Jean Zhang, Julie A. Brennan, Chris G. Kruse, Jan-Hendrik Reinders, Dianne Kowal, Geraldine Ruth Mcfarlane, Feenstra Roelof W, Sara Núñez-García, Andrew C. McCreary, Karen L. Marquis, Radka Graf, Mark H. Pausch, Alexander Greenfield, Margaret Lai, Albert J. Robichaud, Farhana Pruthi, Tikva Carrick, David P. Rotella, Cristina Grosanu, Steven M. Grauer, Rajiah A. Denny, Kelly Sullivan, Rachel Navarra, and Martina A.W. van der Neut
- Subjects
medicine.medical_treatment ,Serotonin reuptake inhibitor ,Clinical Biochemistry ,Carbazoles ,Pharmaceutical Science ,Pharmacology ,Serotonin 5-HT1 Receptor Antagonists ,Biochemistry ,Partial agonist ,chemistry.chemical_compound ,In vivo ,Dopamine receptor D2 ,Drug Discovery ,medicine ,Animals ,Antipsychotic ,Neurotransmitter ,Molecular Biology ,Receptors, Dopamine D2 ,Organic Chemistry ,Rats ,Disease Models, Animal ,chemistry ,Dopamine Agonists ,Receptor, Serotonin, 5-HT1A ,Schizophrenia ,Molecular Medicine ,Serotonin ,Reuptake inhibitor ,Selective Serotonin Reuptake Inhibitors - Abstract
A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.
- Published
- 2009
32. Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist
- Author
-
Zoë A. Hughes, Sheree F. Logue, Zia Ur Rahman, Brian J. Platt, Sharon Rosenzweig-Lipson, Sarah K. Leonard, Jason M. Dwyer, Stacey J. Sukoff Rizzo, Steven M. Grauer, Chad E. Beyer, Robert H. Ring, Claudine Pulicicchio, Lee E. Schechter, Karen L. Marquis, Radka Graf, Bin Luo, and Lynn Resnick
- Subjects
Agonist ,Male ,Reflex, Startle ,Fever ,medicine.drug_class ,CHO Cells ,Pharmacology ,Oxytocin ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,Benzodiazepines ,Mice ,Cricetulus ,Cricetinae ,medicine ,Avoidance Learning ,Animals ,Humans ,Receptor ,Amphetamine ,Maze Learning ,Prepulse inhibition ,Behavior, Animal ,Neural Inhibition ,Oxytocin receptor ,Tail suspension test ,Rats ,Mice, Inbred C57BL ,Acoustic Stimulation ,Anti-Anxiety Agents ,Hindlimb Suspension ,Receptors, Oxytocin ,Pyrazoles ,Psychology ,WAY-267464 ,Stress, Psychological ,medicine.drug ,Protein Binding - Abstract
The widely reported effects of oxytocin (OT) on CNS function has generated considerable interest in the therapeutic potential for targeting this system for a variety of human psychiatric diseases, including anxiety disorders, autism, schizophrenia, and depression. The utility of synthetic OT, as both a research tool and neurotherapeutic, is limited by the physiochemical properties inherent in most neuropeptides, notably its short half-life and poor blood brain barrier penetration. Subsequently, the discovery and development of non-peptide molecules that act as selective agonists of the oxytocin receptor (OTR) has been an important goal of the field. In this study, we report the receptor and behavioral pharmacology of WAY-267464, a first generation small-molecule OTR agonist. WAY-267464 is a high-affinity, potent, and selective (vs. V1a, V2, V1b) agonist of the OTR. In assays measuring both behavioral (four-plate test, elevated zero maze) and autonomic (stress-induced hyperthermia) parameters of the anxiety response, WAY-267464 exhibits an anxiolytic-like profile similar to OT. We have demonstrated that the anxiolytic-like profile of WAY-267464 is mediated through central sites of action. WAY-267464 also significantly reverses disruption in prepulse inhibition of the acoustic startle reflex induced by either MK-801 or amphetamine, similar to the antipsychotic-like effects previously reported for OT. Interestingly, in the mouse tail suspension test, WAY-267464 failed to produce changes in immobility that are seen with OT, raising the question of whether the antidepressant-like activity of OT may be working independently of the OTR. A selective OTR antagonist also failed to block the effects of OT on immobility in the TST. The significance of these findings for shaping the clinical development of OTR agonists is discussed.
- Published
- 2009
33. The orphan GPCR, GPR88, modulates function of the striatal dopamine system: a possible therapeutic target for psychiatric disorders?
- Author
-
Steven M. Grauer, M Amy Sung, Noel Taylor, Karen L. Marquis, Radka Graf, Lynn Zhang, Feng Liu, Zoë A. Hughes, Mark H. Pausch, Sharon Rosenzweig-Lipson, Janet Paulsen, Nicholas J. Brandon, Sheree F. Logue, Brian Bates, and Virginia L. Pulito
- Subjects
Male ,medicine.medical_specialty ,Dopamine and cAMP-Regulated Phosphoprotein 32 ,Reflex, Startle ,Apomorphine ,Dopamine ,Striatum ,Biology ,Nucleus accumbens ,Motor Activity ,Neuropsychological Tests ,Receptors, G-Protein-Coupled ,Cellular and Molecular Neuroscience ,Mice ,Neurochemical ,Internal medicine ,Dopamine receptor D2 ,medicine ,Animals ,Humans ,Psychiatry ,Molecular Biology ,Prepulse inhibition ,Mice, Knockout ,Behavior, Animal ,Receptors, Dopamine D2 ,Brain ,Cell Biology ,Risperidone ,Corpus Striatum ,Stereotypy (non-human) ,Endocrinology ,Dopamine Agonists ,Dopamine Antagonists ,Haloperidol ,Female ,medicine.drug ,Antipsychotic Agents - Abstract
In rodents, the orphan G protein-coupled receptor, Gpr88, is highly expressed in brain regions implicated in the pathophysiology of and is modulated by treatments for schizophrenia. We compared striatal function of Gpr88 knockout mice (Gpr88KOs) to wild-type mice using molecular, neurochemical and behavioral tests. Gpr88KOs lacked expression of Gpr88 in striatum, nucleus accumbens and layer IV of cortex. Gpr88KOs had normal striatal dopamine D2 receptor density and affinity and DARPP-32 expression but Gpr88KOs had higher basal striatal phosphorylated DARPP-32 Thr-34. In vivo microdialysis detected lower basal dopamine in Gpr88KOs while amphetamine-induced dopamine release was normal. Behaviorally, Gpr88KOs demonstrated disrupted prepulse inhibition of startle (PPI) and increased sensitivity to apomorphine-induced climbing and stereotypy (AICS) and amphetamine-stimulated locomotor activity. Antipsychotic administration to Gpr88KOs normalized the PPI deficit and blocked AICS. The modulatory role of Gpr88 in striatal dopamine function suggests it may be a new target for treatments for psychiatric disorders.
- Published
- 2009
34. Schizophrenia-Related Neural and Behavioral Phenotypes in Transgenic Mice Expressing Truncated Disc1
- Author
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Christina Chatzi, Karen L. Marquis, Soh Leh Kuan, Nicholas J. Brandon, Gernot Riedel, David St Clair, Shuisheng He, Orest Hurko, Bing Lang, Feng Zhang, Jin Pu, Chizu Nakamoto, Iain Mackie, Sanbing Shen, Colin D. McCaig, and Mark Day
- Subjects
Positional cloning ,Transgene ,Green Fluorescent Proteins ,Hippocampus ,Mice, Transgenic ,Nerve Tissue Proteins ,Corpus callosum ,DISC1 ,Mice ,medicine ,Neurites ,Animals ,Prefrontal cortex ,Cells, Cultured ,Swimming ,Cerebral Cortex ,Neurons ,Analysis of Variance ,biology ,Behavior, Animal ,General Neuroscience ,Age Factors ,Articles ,Embryo, Mammalian ,Mice, Inbred C57BL ,Disease Models, Animal ,Inhibition, Psychological ,medicine.anatomical_structure ,Parvalbumins ,Phenotype ,Animals, Newborn ,Bromodeoxyuridine ,Gene Expression Regulation ,Hindlimb Suspension ,Cerebral cortex ,Mutation ,biology.protein ,Schizophrenia ,Neuroscience ,Parvalbumin - Abstract
Disrupted-in-Schizophrenia-1(DISC1), identified by positional cloning of a balanced translocation (1;11) with the breakpoint in intron 8 of a large Scottish pedigree, is associated with a range of neuropsychiatric disorders including schizophrenia. To model this mutation in mice, we have generatedDisc1trtransgenic mice expressing 2 copies of truncatedDisc1encoding the first 8 exons using a bacterial artificial chromosome (BAC). With this partial simulation of the human situation, we have discovered a range of phenotypes including a series of novel features not previously reported.Disc1trtransgenic mice display enlarged lateral ventricles, reduced cerebral cortex, partial agenesis of the corpus callosum, and thinning of layers II/III with reduced neural proliferation at midneurogenesis. Parvalbumin GABAergic neurons are reduced in the hippocampus and medial prefrontal cortex, and displaced in the dorsolateral frontal cortex. In culture, transgenic neurons grow fewer and shorter neurites. Behaviorally, transgenic mice exhibit increased immobility and reduced vocalization in depression-related tests, and impairment in conditioning of latent inhibition. These abnormalities inDisc1trtransgenic mice are consistent with findings in severe schizophrenia.
- Published
- 2008
35. Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists
- Author
-
Tikva Carrick, Julia N. Heinrich, John A. Butera, Karen L. Marquis, Scott Christian Mayer, Eugene Tseng, Tim Lock, Shaiu-Ching Sun, Albert J. Uveges, Dianne Kowal, Angela Kramer, Mark H. Pausch, and Michael Popiolek
- Subjects
Pharmacology ,Agonist ,Receptor, Muscarinic M3 ,medicine.medical_specialty ,Chemistry ,medicine.drug_class ,Receptors, Dopamine D2 ,Receptor, Muscarinic M1 ,Muscarinic acetylcholine receptor M1 ,Muscarinic Agonists ,Talsaclidine ,Sabcomeline ,Ligands ,Cevimeline ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Muscarinic acetylcholine receptor ,Receptor, Serotonin, 5-HT2B ,medicine ,Muscarinic acetylcholine receptor M4 ,Xanomeline ,medicine.drug ,Protein Binding - Abstract
In functional assay assessments using the five muscarinic receptor subtypes, a second generation of muscarinic M(1)-preferring receptor agonists [AC-42 (1), AC-260584 (2), 77-LH-28-1 (3) and LY-593039 (4)] was shown to have higher selectivity for muscarinic M(1) over M(3) receptor as compared to historical agonists [talsaclidine (8), sabcomeline (10), xanomeline (11), WAY-132983 (12), cevimeline (9) and NGX-267 (6)]. Another striking difference of these more recent compounds is their affinities for the dopamine D(2) and 5-HT(2B) receptors. Taken together, these results suggest that the newer compounds may have a greater clinical safety profile, especially with regard to muscarinic M(3) receptor-mediated events, than the historical agonists, but their affinities for other receptors may still compromise their use to validate the therapeutic potential of muscarinic M(1) receptor agonists.
- Published
- 2008
36. 5-HT2C receptor agonists as an innovative approach for psychiatric disorders
- Author
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Sharon Rosenzweig-Lipson, Karen L. Marquis, and John Dunlop
- Subjects
medicine.medical_specialty ,Depressive Disorder ,business.industry ,medicine.disease ,Serotonin Receptor Agonists ,5-HT2C receptor ,RNA editing ,Schizophrenia ,Drug Design ,medicine ,Serotonin 5-HT2 Receptor Antagonists ,Receptor, Serotonin, 5-HT2C ,Animals ,Humans ,Serotonin Antagonists ,Signal transduction ,Psychiatry ,Receptor ,business ,Serotonin 5-HT2 Receptor Agonists ,Signal Transduction - Abstract
Modulating activity at the 5-HT(2C) receptor holds a tremendous amount of therapeutic promise in multiple psychiatric indications. However, the signaling and regulation of the 5-HT(2C) receptor is highly complex due to multiple signaling pathways and agonist-directed trafficking of this receptor. Moreover, the 5-HT(2C) receptor is differentially regulated via RNA editing in multiple psychiatric disorders and following either pharmacological or environmental manipulation. Direct and indirect data suggest that both agonists and antagonists may provide benefits in several disorders. The current review highlights the underlying complexities of this area and provides the rationale for using 5-HT(2C) agonists in the treatment of both schizophrenia and depressive disorders.
- Published
- 2008
37. Discovery of N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine as a potent, selective, and orally active 5-HT(6) receptor agonist
- Author
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William Joseph Lennox, John W. Ellingboe, Deborah L. Smith, Derek Cecil Cole, Joseph Raymond Stock, and Chad E. Beyer, Louis Leung, Ronald C. Bernotas, Galante Rocco John, Pingzhong Huang, Lee A. Dawson, Michael F. Kelly, Steve Boikess, Xidong Feng, Lee E. Schechter, Karen L. Marquis, Sharon Rosenzweig-Lipson, Joseph Coupet, and Guoming Zhang
- Subjects
Agonist ,Tryptamine ,Stereochemistry ,medicine.drug_class ,Microdialysis ,Administration, Oral ,Biological Availability ,CHO Cells ,Pharmacology ,In Vitro Techniques ,chemistry.chemical_compound ,Mice ,Radioligand Assay ,Structure-Activity Relationship ,Cricetulus ,Dogs ,Cricetinae ,Drug Discovery ,medicine ,Animals ,Humans ,Thiazole ,Receptor ,Ion channel ,gamma-Aminobutyric Acid ,Sulfonyl ,chemistry.chemical_classification ,Biological activity ,Haplorhini ,Tryptamines ,Frontal Lobe ,Rats ,Serotonin Receptor Agonists ,Thiazoles ,chemistry ,Solubility ,Receptors, Serotonin ,5-HT6 receptor ,Microsomes, Liver ,Molecular Medicine - Abstract
N1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT6 Ki = 2 nM, EC50 = 6.5 nM, Emax = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders.
- Published
- 2007
38. Aplindore (DAB-452), a high affinity selective dopamine D2 receptor partial agonist
- Author
-
Geoff Hornby, Margaret Lai, Li-Xin Jiang, Terrance H. Andree, Gary Paul Stack, Julia N. Heinrich, Michael Popiolek, Mark H. Pausch, Julie A. Brennan, Kelly Sullivan, and Karen L. Marquis
- Subjects
Aplindore ,Male ,Indoles ,Quinpirole ,medicine.drug_class ,CHO Cells ,Biology ,Motor Activity ,Partial agonist ,Binding, Competitive ,Rats, Sprague-Dawley ,Radioligand Assay ,Dopamine receptor D1 ,Cricetulus ,Dopamine receptor D2 ,Cricetinae ,Receptors, Adrenergic, alpha-1 ,medicine ,Animals ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Oxidopamine ,Pharmacology ,Raclopride ,Dose-Response Relationship, Drug ,Receptors, Dopamine D2 ,Dopaminergic ,Receptors, Dopamine D4 ,Receptor antagonist ,Molecular biology ,GTP-Binding Protein alpha Subunits ,Rats ,Substantia Nigra ,Guanosine 5'-O-(3-Thiotriphosphate) ,Dopamine Agonists ,Receptor, Serotonin, 5-HT1A ,Calcium ,Receptors, Serotonin, 5-HT2 ,Endogenous agonist ,medicine.drug - Abstract
The pharmacology of aplindore (DAB-452) was characterized in CHO-K1 cells stably transfected with the human dopamine D(2) receptor short isoform (CHO-D(2s)) and in a behavioral model for post-synaptic agonism in rats. In [(3)H]-spiperone competition binding studies, aplindore showed high affinity for dopamine D(2) and D(3) receptors and low affinity for the dopamine D(4), serotonin (5-HT)(1A), 5-HT(2) receptors and the alpha1-adrenoceptor. The high potency partial agonist activity of aplindore was demonstrated in [(35)S]guanosine 5'-O-(3-thiotriphosphate) ([(35)S]GTPgammaS) binding, extracellular signal-regulated kinase (ERK)-phosphorylation and intracellular calcium flux assay using fluorometric plate reader ([Ca(2+)](i)-FLIPR) format. The [Ca(2+)](i)-FLIPR assay was conducted with CHO-D(2S) receptor cells also stably expressing chimeric G(alphaq/o)-proteins. In all assay modalities, the potencies and intrinsic activities of aplindore were lower than dopamine and higher than aripiprazole. In contrast to the [(35)S]GTPgammaS binding and ERK-phosphorylation assays, the [Ca(2+)](i)-FLIPR assay was able to detect the low partial agonist activity of SDZ 208-912. In unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, aplindore induced contralateral turning, which was blocked by the dopamine D(2) receptor antagonist raclopride. The dopamine D(2) receptor selective partial agonist profile of aplindore suggests that it should be effective for the treatment of dopaminergic-based disorders, such as schizophrenia and Parkinson's disease.
- Published
- 2006
39. P.3.d.005 Activity of phosphodiesterase 10A inhibitors in a novel animal model of negative symptoms of schizophrenia
- Author
-
H. Stange, Karen L. Marquis, T. Hage, D. Zschaber, B. Langen, and Nicholas J. Brandon
- Subjects
Pharmacology ,business.industry ,Schizophrenia (object-oriented programming) ,Phosphodiesterase ,Bioinformatics ,Psychiatry and Mental health ,Animal model ,Neurology ,Medicine ,Pharmacology (medical) ,Neurology (clinical) ,business ,Biological Psychiatry ,Clinical psychology - Published
- 2010
40. Synthesis and SAR of adatanserin: novel adamantyl aryl- and heteroarylpiperazines with dual serotonin 5-HT(1A) and 5-HT(2) activity as potential anxiolytic and antidepressant agents
- Author
-
Magid Abou-Gharbia, Herman Morris, Terrance H. Andree, John P. Yardley, Robert J. Kucharik, Horace Fletcher, Rosemary Scerni, Georgia B. McGaughey, Michael Byron Webb, Wayne E. Childers, Carl A. Boast, John A. Moyer, Karen L. Marquis, and Usha R. Patel
- Subjects
Male ,Models, Molecular ,Adatanserin ,Stereochemistry ,Chemistry ,Spectrum Analysis ,Serotonergic ,Chemical synthesis ,Antidepressive Agents ,Piperazines ,Rats ,Rats, Sprague-Dawley ,Radioligand Assay ,Structure-Activity Relationship ,Anti-Anxiety Agents ,Dopamine receptor D2 ,Receptors, Serotonin ,Drug Discovery ,Molecular Medicine ,Animals ,Serotonin ,Binding site ,Receptor ,5-HT receptor - Abstract
Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared and examined in various receptor binding and behavioral tests to determine their serotonin receptor activities. Many compounds demonstrated modest to high affinity for 5-HT(1A) receptors, with compounds 9, 13, 23, 33, 34, and 43 being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively high affinity for 5-HT(1A) receptors (K(i) = 8 nM) and acceptable selectivity versus D(2) receptors (K(i) = 708 mM); however, it lacked in vivo activity in serotonergic behavioral models. In contrast, compounds 9 (WY-50,324, SEB-324, adatanserin), adamantyl-1-carboxylic acid 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamide, and 13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamide, demonstrated high affinity for 5-HT(1A) binding sites (K(i) = 1 nM for both) and moderate affinity for 5-HT(2) receptors (K(i) = 73 and 75 nM, respectively). Both compounds also demonstrated partial 5-HT(1A) agonist activity in vivo in rat serotonin syndrome and 5-HT(2) antagonist activity in quipazine- and DOI-induced head shake paradigms. The selective 5-HT(1A) partial agonist and 5-HT(2) antagonist activity of 9 was accompanied by significant anxiolytic activity in an animal conflict model. On the basis of this profile, compound 9 entered development as a combined anxiolytic and antidepressant agent.
- Published
- 1999
41. New generation dopaminergic agents. 7. Heterocyclic bioisosteres that exploit the 3-OH-phenoxyethylamine D2 template
- Author
-
Hossein Mazandarani, Joseph Coupet, Richard Eric Mewshaw, Terrance H. Andree, Julie A. Brennan, Xiaojie Shi, Karen L. Marquis, James Albert Nelson, and Uresh Shantilal Shah
- Subjects
Agonist ,Stereochemistry ,medicine.drug_class ,Clinical Biochemistry ,Dopamine Agents ,Pharmaceutical Science ,Motor Activity ,Biochemistry ,Chemical synthesis ,Partial agonist ,Mice ,Dopamine ,Drug Discovery ,medicine ,Animals ,Receptor ,Molecular Biology ,Bicyclic molecule ,Chemistry ,Receptors, Dopamine D2 ,Organic Chemistry ,Dopaminergic ,Molecular Medicine ,Benzimidazoles ,Selectivity ,medicine.drug - Abstract
The synthesis of several-bioisosteric analogs based on the 3-OH-phenoxyethylamine dopamine D 2 agonist template (i.e., 3 ) is described. The benzimidazol-2-ones and benzthioimidazol-2-ones ( 7–10 ) and 2-trifluoromethyl-benzimidazole ( 13 ) were observed to have excellent affinity for the D 2 receptor.
- Published
- 1999
42. New generation dopaminergic agents. 6. Structure-activity relationship studies of a series of 4-(aminoethoxy)indole and 4-(aminoethoxy)indolone derivatives based on the newly discovered 3-hydroxyphenoxyethylamine D2 template
- Author
-
Julie A. Brennan, Michael Byron Webb, Richard Eric Mewshaw, Rosemary Scerni, Karen L. Marquis, Theodore Wasik, Xiaojie Shi, Terrance H. Andree, and Georgia B. McGaughey
- Subjects
Agonist ,Models, Molecular ,Indoles ,Molecular model ,Intrinsic activity ,Stereochemistry ,medicine.drug_class ,Molecular Conformation ,In Vitro Techniques ,Motor Activity ,Chemical synthesis ,Binding, Competitive ,Hippocampus ,chemistry.chemical_compound ,Mice ,Radioligand Assay ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Ethylamines ,Structure–activity relationship ,Animals ,Indole test ,Bicyclic molecule ,Chemistry ,Receptors, Dopamine D2 ,Corpus Striatum ,Rats ,Dopamine Agonists ,Lactam ,Molecular Medicine ,Stereotyped Behavior - Abstract
A series of 4-(aminoethoxy)indoles 7 and a related series of 4-(aminoethoxy)indolones 8 were synthesized and evaluated for their affinity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 4-aminoethoxy derivatives (i.e., 7 and 8) were designed as bioisosteric analogues based on the phenol prototype 4. The indolones 8 were observed to have high affinity for the D2High receptor. Comparison of their previously reported chroman analogues with the more flexible 4-(aminoethoxy)indoles revealed the chroman analogues to be more potent, whereas little loss in D2High affinity was observed when comparing the 4-(aminoethoxy)indolones with their respective chroman analogues. Several regions of the phenoxyethylamine framework were modified and recognized as potential sites to modulate the level of intrinsic activity. A conformational analysis was performed and a putative bioactive conformation was proposed which fulfilled the D2 agonist pharmacophore criteria based on the McDermed model. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.
- Published
- 1999
43. New generation dopaminergic agents. 2. Discovery of 3-OH-phenoxyethylamine and 3-OH-N1-phenylpiperazine dopaminergic templates
- Author
-
Morris Husbands, Xiaojie Shi, Elizabeth S. Gildersleeve, Julie A. Brennan, Terrance H. Andree, Karen L. Marquis, Rafal Ochalski, Joseph Coupet, Hossein Mazandarani, Magid Abou-Gharbia, Mark I. Cockett, Michael Byron Webb, Richard Eric Mewshaw, and Georgia B. McGaughey
- Subjects
Stereochemistry ,Receptors, Dopamine D2 ,Organic Chemistry ,Clinical Biochemistry ,Dopaminergic ,Pharmaceutical Science ,Phenylpiperazine ,Biochemistry ,Partial agonist ,Piperazines ,chemistry.chemical_compound ,Structure-Activity Relationship ,Template ,chemistry ,Phenols ,Dopamine receptor D2 ,Drug Discovery ,Benzene derivatives ,Dopamine Agonists ,Molecular Medicine ,Structure–activity relationship ,Molecular Biology - Abstract
Described in this report is a systematic study which led to the identification of two new dopamine D2 partial agonists (5 and 17). Phenols 5 and 17 represent prototypes of two new classes of D2 partial agonists as well as templates for the future design of novel dopaminergic agents.
- Published
- 1999
44. New generation dopaminergic agents. 1. Discovery of a novel scaffold which embraces the D2 agonist pharmacophore. Structure-activity relationships of a series of 2-(aminomethyl)chromans
- Author
-
Magid Abou-Gharbia, Luz Cortes-Burgos, Rafal Ochalski, Alan H. Katz, Kang Young Hee, Mark I. Cockett, Michael J. Piesla, Theodore Wasik, Michael Z. Kagan, Richard Eric Mewshaw, Rosemary Scerni, Hossein Mazandarani, Michael Byron Webb, Xiaojie Shi, Joseph Coupet, Karen L. Marquis, Anna Park, Taylor Spangler, Terrance H. Andree, Joseph Kavanagh, Julie A. Brennan, and Gary Paul Stack
- Subjects
Agonist ,Models, Molecular ,Magnetic Resonance Spectroscopy ,Molecular model ,Stereochemistry ,medicine.drug_class ,Dopamine Agents ,Mice, Inbred Strains ,CHO Cells ,Motor Activity ,Chemical synthesis ,Partial agonist ,Mass Spectrometry ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,Cricetinae ,Drug Discovery ,medicine ,Animals ,Chromans ,Bicyclic molecule ,Molecular Structure ,Chemistry ,Receptors, Dopamine D2 ,Dopaminergic ,Stereoisomerism ,Rats ,Receptors, Serotonin ,Molecular Medicine ,Pharmacophore ,Selectivity ,Protein Binding - Abstract
A series of 2-(aminomethyl)chromans (2-AMCs) was synthesized and evaluated for their affinity and selectivity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 7-hydroxy-2-(aminomethyl)chroman moiety was observed to be the primary D2 agonist pharmacophore. The 2-methylchroman moiety was discovered to be an entirely novel scaffold which could be used to access the D2 agonist pharmacophore. Attaching various simple alkyl and arylalkyl side chains to the 7-hydroxy 2-AMC nucleus had significant effects on selectivity for the D2High receptor vs the 5HT1A and alpha 1 receptors. A novel DA partial agonist, (R)-(-)-2-(benzylamino)methyl)chroman-7-ol [R-(-)-35c], was identified as having the highest affinity and best selectivity for the D2High receptor vs the alpha 1 and 5HT1A receptors. Several regions of the 2-AMC nucleus were modified and recognized as potential sites to modulate the level of intrinsic activity. The global minimum conformer of the 7-hydroxy-2-AMC moiety was identified as fulfilling the McDermed model D2 agonist pharmacophoric criteria and was proposed as the D2 receptor-bound conformation. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.
- Published
- 1998
45. COMPOUND 1, A POTENT AND SELECTIVE DAO INHIBITOR, DEMONSTRATES EFFICACY IN SEVERAL PRECLINICAL ANIMAL MODELS OF SCHIZOPHRENIA
- Author
-
Steven M. Grauer, Rachel Navarra, Julie A. Brennan, Michael Popiolek, John A. Butera, Joseph Zaccardi, Girija Krishnamurthy, Karen L. Marquis, Paul Jeffrey Dollings, Mark H. Pausch, Keith Pitts, and Nicholas J. Brandon
- Subjects
Psychiatry and Mental health ,business.industry ,Animal models of schizophrenia ,Medicine ,Pharmacology ,business ,Biological Psychiatry - Published
- 2010
46. Cholecystokinin octapeptide alters morphine-induced effects on EEG power spectra both quantitatively and qualitatively
- Author
-
Helen Stamidis, Karen L. Marquis, Gerald A. Young, and Gail M. Hudson
- Subjects
medicine.medical_specialty ,Neuropeptide ,Electroencephalography ,Peptide hormone ,Sincalide ,Rats, Sprague-Dawley ,Bursting ,Internal medicine ,medicine ,Animals ,Cholecystokinin ,Injections, Intraventricular ,Pharmacology ,medicine.diagnostic_test ,Morphine ,Chemistry ,Enkephalins ,Rats ,Electrophysiology ,Endocrinology ,Gastrointestinal hormone ,Anesthesia ,Female ,Enkephalin, D-Penicillamine (2,5) ,medicine.drug - Abstract
In the present study, EEG analysis was used to determine if cholecystokinin octapeptide (CCK-8) has an effect on the EEG spectral profile associated with morphine-induced bursting. Adult female Sprague-Dawley rats were implanted with cortical electrodes and indwelling i.c.v. and i.v. cannulas. On the day of the experiment, each rat received an i.c.v. injection of either H2O or one of four doses of CCK-8: 8.0, 16.0, 32.0 or 64.0 ng. Ten minutes after receiving the i.c.v. injection, each rat received a 10.0 mg/kg dose of morphine by i.v. injection. Neither the i.c.v. injections of H2O nor CCK-8 produced any EEG bursting or behavioral stupor. However, the i.v. injection of morphine produced high-voltage, slow-wave EEG bursts in all rats. Analysis of EEG recorded during bursting showed that both the 32.0 and 64.0 ng doses of CCK-8 increased absolute power associated with morphine-induced bursting, and comparison of the distribution of power across the range of frequency bands between the control (H2O) and the 32.0 ng dose of CCK-8 revealed that CCK-8 caused a significant change in the pattern of distribution of power. Furthermore, significant dose-related differences were found in the global (1-50 Hz) parameters absolute power, mean frequency, mobility, complexity and edge frequency. Significant differences among the five groups were not found in the parameter of peak frequency, or in either latency to slow-wave sleep or duration of morphine-induced bursting. These results demonstrate that CCK-8 caused both quantitative and qualitative changes in the EEG spectral profile associated with morphine-induced bursting.
- Published
- 1992
47. Characterization of the alpha-7 nicotinic receptor agonist WYE-103914 in models relevant to schizophrenia and interaction with antipsychotics
- Author
-
Tom Comery, John Dunlop, Steven C. Leiser, Renza Roncarati, Cody Kelley, Steven M. Grauer, Simon Haydar, Georg C. Terstappen, C. Scali, Karen L. Marquis, Rachel Navarra, Claudine Pulicicchio, C. Ghiron, Albert J. Robichaud, and Boyd L. Harrison
- Subjects
Pharmacology ,Agonist ,Nicotinic agonist ,Chemistry ,medicine.drug_class ,Schizophrenia ,medicine ,Alpha-7 nicotinic receptor ,medicine.disease ,Biochemistry - Published
- 2009
48. In vitro pharmacological characterization and pro-cognitive effects of the selective alpha-7 nicotinic agonist WYE-103914
- Author
-
John Dunlop, Albert J. Robichaud, Sarita Yeola, Karen L. Marquis, Renza Roncarati, Tom Comery, Qian Lin, Georg C. Terstappen, C. Scali, Boyd L. Harrison, Angela Kramer, C. Ghiron, Julie A. Brennan, Tim Lock, S. Aschmies, Flora Jow, Cody Kelley, Simon Haydar, Chad E. Beyer, and Dianne Kowal
- Subjects
Pharmacology ,Nicotinic agonist ,Chemistry ,Alpha (ethology) ,Inverse agonist ,Biochemistry ,In vitro - Published
- 2009
49. P.3.d.019 Vabicaserin: effects of a novel 5-HT2C agonist on medial prefrontal cortex neurotransmission, cognition and sensorimotor gating
- Author
-
G. Stack, S. Aschmies, Sharon Rosenzweig-Lipson, S. Grauer, T. Comery, Qian Lin, M.Y. Zhang, Chad E. Beyer, Z. Hughes, and Karen L. Marquis
- Subjects
Pharmacology ,Agonist ,business.industry ,medicine.drug_class ,Sensorimotor Gating ,Cognition ,Vabicaserin ,Neurotransmission ,Psychiatry and Mental health ,Neurology ,Medicine ,Pharmacology (medical) ,Neurology (clinical) ,business ,Prefrontal cortex ,Consumer neuroscience ,Neuroscience ,Biological Psychiatry - Published
- 2007
50. A comparison of functional mGluR ligand activity in a cho cell line expressing hmGluR2 using forskolin-stimulated cAMP accumulation and [35S]GTPγS binding assays
- Author
-
Dianne Kowal, J.R. Tasse, and Karen L. Marquis
- Subjects
Pharmacology ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Forskolin ,Chemistry ,Metabotropic glutamate receptor ,Chinese hamster ovary cell ,Line (text file) ,Ligand (biochemistry) ,Cell biology ,Gtpγs binding - Published
- 1996
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