72 results on '"Cosford ND"'
Search Results
52. Discovery of highly potent, selective, orally bioavailable, metabotropic glutamate subtype 5 (mGlu5) receptor antagonists devoid of cytochrome P450 1A2 inhibitory activity.
- Author
-
Smith ND, Poon SF, Huang D, Green M, King C, Tehrani L, Roppe JR, Chung J, Chapman DP, Cramer M, and Cosford ND
- Subjects
- Administration, Oral, Animals, Anti-Anxiety Agents chemical synthesis, Anti-Anxiety Agents chemistry, Anti-Anxiety Agents pharmacokinetics, Biological Availability, Molecular Structure, Rats, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship, Tetrazoles chemistry, Cytochrome P-450 CYP1A2 Inhibitors, Receptors, Metabotropic Glutamate antagonists & inhibitors, Tetrazoles chemical synthesis, Tetrazoles pharmacokinetics
- Abstract
Structure-activity relationship studies focused on bio-isosteric replacements of 2-pyridyl resulted in mGlu5 receptor antagonists with reduced inhibition of cytochrome P450 1A2. This led to highly potent, selective and orally bioavailable 2-imidazolyl tetrazoles such as (10) that are devoid of cytochrome P450 inhibitory activity.
- Published
- 2004
- Full Text
- View/download PDF
53. 3-[3-Fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine: a highly potent and orally bioavailable metabotropic glutamate subtype 5 (mGlu5) receptor antagonist.
- Author
-
Poon SF, Eastman BW, Chapman DF, Chung J, Cramer M, Holtz G, Cosford ND, and Smith ND
- Subjects
- Administration, Oral, Animals, Anti-Anxiety Agents administration & dosage, Anti-Anxiety Agents chemical synthesis, Biological Availability, Molecular Structure, Nitriles chemistry, Nitriles pharmacokinetics, Pyridines chemistry, Pyridines pharmacokinetics, Rats, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship, Tetrazoles chemistry, Tetrazoles pharmacokinetics, Anti-Anxiety Agents pharmacokinetics, Nitriles chemical synthesis, Pyridines chemical synthesis, Receptors, Metabotropic Glutamate antagonists & inhibitors, Tetrazoles chemical synthesis
- Abstract
Structure-activity relationship studies performed around 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile for the purpose of developing novel mGlu5 receptor antagonists are described. Synthesis of a series of four-ring tetrazoles led to the discovery of 3-[3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine, a highly potent, brain penetrant, azole-based mGlu5 receptor antagonist.
- Published
- 2004
- Full Text
- View/download PDF
54. The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in rodent models of anxiety.
- Author
-
Busse CS, Brodkin J, Tattersall D, Anderson JJ, Warren N, Tehrani L, Bristow LJ, Varney MA, and Cosford ND
- Subjects
- Animals, Anxiety metabolism, Dose-Response Relationship, Drug, Male, Mice, Pyridines chemistry, Pyridines metabolism, Rats, Rats, Sprague-Dawley, Rats, Wistar, Receptor, Metabotropic Glutamate 5, Thiazoles chemistry, Thiazoles metabolism, Anxiety drug therapy, Disease Models, Animal, Pyridines therapeutic use, Receptors, Metabotropic Glutamate antagonists & inhibitors, Receptors, Metabotropic Glutamate metabolism, Thiazoles therapeutic use
- Abstract
Previous reports have demonstrated the anxiolytic effect of the potent and systemically active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in rodents. Here, we present evidence for the anxiolytic activity of a novel mGlu5 receptor antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), in rats and compare its profile to the benzodiazepine receptor agonist diazepam. MTEP occupied mGlu5 receptors in a dose-dependent manner with essentially full receptor occupancy at the highest dose tested (10 mg/kg, i.p.). At doses appropriate for mGlu5 receptor-mediated effects, MTEP significantly reduced fear-potentiated startle and increased punished responding in a modified Geller-Seifter conflict model consistent with an anxiolytic-like profile. In both models, the magnitude of the anxiolytic-like response was similar to that seen with diazepam. In contrast, MTEP decreased unpunished responding to a lesser extent than diazepam and had no effect on rotarod performance when administered either alone or in combination with ethanol. Repeated dosing with MTEP in this model eliminated the increase in punished responding observed with acute dosing. The present results suggest that mGlu5 receptor antagonists lack the side effects seen with benzodiazepines, such as sedation and ethanol interaction, and provide insight into a possible role for mGlu5 receptor antagonists in the modulation of mood disorders.
- Published
- 2004
- Full Text
- View/download PDF
55. Pyrimidine methyl anilines: selective potentiators for the metabotropic glutamate 2 receptor.
- Author
-
Hu E, Chua PC, Tehrani L, Nagasawa JY, Pinkerton AB, Rowe BA, Vernier JM, Hutchinson JH, and Cosford ND
- Subjects
- Aniline Compounds chemistry, Aniline Compounds pharmacology, Pyrimidines chemistry, Pyrimidines pharmacology, Radioligand Assay, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides chemistry, Sulfonamides pharmacology, Aniline Compounds chemical synthesis, Pyrimidines chemical synthesis, Receptors, Metabotropic Glutamate agonists
- Abstract
Pyrimidine methyl anilines as potent and selective mGlu2 potentiators are described. Findings from the structure-activity-relationship investigations are discussed.
- Published
- 2004
- Full Text
- View/download PDF
56. Discovery of novel heteroarylazoles that are metabotropic glutamate subtype 5 receptor antagonists with anxiolytic activity.
- Author
-
Roppe J, Smith ND, Huang D, Tehrani L, Wang B, Anderson J, Brodkin J, Chung J, Jiang X, King C, Munoz B, Varney MA, Prasit P, and Cosford ND
- Subjects
- Animals, Anti-Anxiety Agents administration & dosage, Anti-Anxiety Agents chemistry, Molecular Structure, Rats, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship, Anti-Anxiety Agents chemical synthesis, Anti-Anxiety Agents pharmacology, Receptors, Metabotropic Glutamate antagonists & inhibitors
- Abstract
The highly potent, selective, and brain-penetrant metabotropic glutamate subtype 5 (mGlu5) receptor antagonists 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (47) and 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (48) are reported. Compound 47 is active in the rat fear-potentiated startle (FPS) model of anxiety with ED(50) = 5.4 mg/kg (po) when dosed acutely. In this model the anxiolytic effects of 47 rapidly tolerate on repeated dosing.
- Published
- 2004
- Full Text
- View/download PDF
57. Anxiolytic-like effects of MTEP, a potent and selective mGlu5 receptor agonist does not involve GABA(A) signaling.
- Author
-
Klodzinska A, Tatarczyńska E, Chojnacka-Wójcik E, Nowak G, Cosford ND, and Pilc A
- Subjects
- Animals, Diazepam pharmacology, Dose-Response Relationship, Drug, Drinking drug effects, Drinking Behavior drug effects, Drinking Behavior physiology, Drug Interactions, Electroshock methods, Exploratory Behavior drug effects, Flumazenil pharmacology, GABA Modulators pharmacology, Male, Maze Learning drug effects, Mice, Rats, Rats, Wistar, Receptor, Metabotropic Glutamate 5, Sensory Thresholds drug effects, Signal Transduction physiology, Behavior, Animal drug effects, Pyridines pharmacology, Receptors, GABA-A metabolism, Receptors, Metabotropic Glutamate agonists, Signal Transduction drug effects, Thiazoles pharmacology
- Abstract
Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic drugs including the involvement of group I metabotropic glutamate (mGlu) receptors. Given the recent discovery of a selective and brain penetrable mGlu5 receptor antagonists, the effect of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), i.e. the most potent mGlu5 antagonist, was evaluated in established models of anxiety after single or repeated administration. We also studied if the anxiolytic effect of MTEP is mediated by mechanism involving the GABA-benzodiazepine (BZD) receptor complex. Experiments were performed on male Wistar rats or male Albino Swiss mice. The anxiolytic-like effects of MTEP were tested in the conflict drinking test and the elevated plus-maze test in rats as well as in the four-plate test in mice. MTEP (0.3-3.0 mg/kg) induced anxiolytic-like effects in the conflict drinking test (after single and repeated administration) and in the elevated plus-maze test in rats. In the four-plate test in mice, it exerted anxiolytic activity at a dose of 20 mg/kg. MTEP had no effect on the locomotor activity of animals. The anxiolytic-like effect of MTEP was not changed by BZD antagonist flumazenil. Moreover, a synergistic interaction between non-effective doses of MTEP and diazepam was observed in the conflict drinking test. These data suggest that selective mGlu5 receptor antagonists mediated anxiolysis is not dependent on GABA-ergic system and that these agents may play a role in the therapy of anxiety.
- Published
- 2004
- Full Text
- View/download PDF
58. 5-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-2,3'-bipyridine: a highly potent, orally active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist with anxiolytic activity.
- Author
-
Roppe JR, Wang B, Huang D, Tehrani L, Kamenecka T, Schweiger EJ, Anderson JJ, Brodkin J, Jiang X, Cramer M, Chung J, Reyes-Manalo G, Munoz B, and Cosford ND
- Subjects
- Animals, Anti-Anxiety Agents chemistry, Anti-Anxiety Agents pharmacokinetics, Anti-Anxiety Agents pharmacology, Anxiety, Disease Models, Animal, Excitatory Amino Acid Antagonists chemical synthesis, Excitatory Amino Acid Antagonists chemistry, Kinetics, Models, Molecular, Pyridines chemistry, Pyridines pharmacokinetics, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate drug effects, Structure-Activity Relationship, Thiazoles chemistry, Thiazoles pharmacokinetics, Thiazoles pharmacology, Anti-Anxiety Agents chemical synthesis, Excitatory Amino Acid Antagonists pharmacology, Pyridines chemical synthesis, Pyridines pharmacology, Receptors, Metabotropic Glutamate physiology, Thiazoles chemical synthesis
- Abstract
Structure-activity relationship studies leading to the discovery of a new, orally active mGlu5 receptor antagonist are described. The title compound, 5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2,3'-bipyridine, is highly potent in vitro, has good in vivo receptor occupancy, and is efficacious in the rat fear-potentiated startle model of anxiety following oral dosing.
- Published
- 2004
- Full Text
- View/download PDF
59. In vivo receptor occupancy of mGlu5 receptor antagonists using the novel radioligand [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine).
- Author
-
Anderson JJ, Bradbury MJ, Giracello DR, Chapman DF, Holtz G, Roppe J, King C, Cosford ND, and Varney MA
- Subjects
- Animals, Binding Sites, Hippocampus metabolism, Injections, Intraperitoneal, Injections, Intravenous, Ligands, Male, Mice, Mice, Inbred C57BL, Prosencephalon metabolism, Pyridines metabolism, Radioligand Assay methods, Rats, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate genetics, Species Specificity, Thiazoles metabolism, Thiazoles pharmacology, Time Factors, Tritium, Pyridines pharmacology, Receptors, Metabotropic Glutamate antagonists & inhibitors, Receptors, Metabotropic Glutamate metabolism
- Abstract
In vivo receptor occupancy of mGlu5 receptor antagonists was quantified in rat and mouse brain using the mGlu5 receptor selective antagonist [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine) ([3H]methoxy-PEPy). Administration of [3H]methoxy-PEPy (50 microCi/kg i.v.) to mGlu5 receptor-deficient mice revealed binding at background levels in forebrain, whereas wild-type mice exhibited 14-fold higher binding in forebrain relative to cerebellum. Systemic administration of the mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) reduced the binding of [3H]methoxy-PEPy in rats and mice, reflecting mGlu5 receptor occupancy by these compounds. MPEP (10 mg/kg i.p.) and MTEP (3 mg/kg i.p.) maintained >75% receptor occupancy for 2 h in rats, while in mice MPEP and MTEP achieved >75% occupancy for only 30 and 15 min, respectively. Compound levels in plasma were substantially lower in mice suggesting species differences in receptor occupancy result from differences in absorption or metabolism of the compounds. These findings demonstrate that [3H]methoxy-PEPy is useful for determining the occupancy of mGlu5 receptors in the brain.
- Published
- 2003
- Full Text
- View/download PDF
60. Identification of metabotropic glutamate receptor antagonists using an automated high-throughput screening system.
- Author
-
Hodder P, Cassaday J, Peltier R, Berry K, Inglese J, Feuston B, Culberson C, Bleicher L, Cosford ND, Bayly C, Suto C, Varney M, and Strulovici B
- Subjects
- Calcium chemistry, Calcium metabolism, Cell Line, Dose-Response Relationship, Drug, Excitatory Amino Acid Antagonists analysis, Fluorescence, Fluorescent Dyes chemistry, Fluorometry instrumentation, Glutamic Acid chemistry, Glutamic Acid pharmacology, Humans, Intracellular Fluid chemistry, Intracellular Fluid metabolism, Kinetics, Photomicrography, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate agonists, Sensitivity and Specificity, Transfection, Calcium analysis, Excitatory Amino Acid Antagonists pharmacology, Fluorometry methods, Receptors, Metabotropic Glutamate antagonists & inhibitors
- Abstract
Antagonists to the human metabotropic glutamate receptor subtype 5a(mGluR(5a)) have been implicated as potential therapeutics for the treatment of a variety of nervous system disorders, including pain, anxiety, and Parkinson's disease. To discover novel antagonists to the mGluR(5a), a functional assay measuring agonist-induced intracellular calcium release was developed. The assay was used for the high-throughput screening of a large collection of compounds in single wells using a fully automated robotic platform. Primary high-throughput screening hits were subjected to a combination of data analysis and counterscreening assays to identify several compounds with both efficacy and selectivity for the metabotropic glutamate receptor target.
- Published
- 2003
- Full Text
- View/download PDF
61. [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy: potent and selective radioligands for the metabotropic glutamate subtype 5 (mGlu5) receptor.
- Author
-
Cosford ND, Roppe J, Tehrani L, Schweiger EJ, Seiders TJ, Chaudary A, Rao S, and Varney MA
- Subjects
- Animals, Binding Sites, Brain drug effects, Brain metabolism, Chemical Phenomena, Chemistry, Physical, Humans, In Vitro Techniques, Ligands, Male, Pyridines pharmacokinetics, Radiopharmaceuticals pharmacokinetics, Rats, Receptor, Metabotropic Glutamate 5, Thiazoles pharmacokinetics, Pyridines pharmacology, Radiopharmaceuticals pharmacology, Receptors, Metabotropic Glutamate drug effects, Thiazoles pharmacology
- Abstract
The design, synthesis, and characterization of two potent, non-competitive radioligands, [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy, that are selective for the mGlu5 receptor are described.
- Published
- 2003
- Full Text
- View/download PDF
62. 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity.
- Author
-
Cosford ND, Tehrani L, Roppe J, Schweiger E, Smith ND, Anderson J, Bristow L, Brodkin J, Jiang X, McDonald I, Rao S, Washburn M, and Varney MA
- Subjects
- Anti-Anxiety Agents chemistry, Anti-Anxiety Agents pharmacology, Anxiety psychology, Brain metabolism, Calcium metabolism, Cell Line, Excitatory Amino Acid Antagonists chemistry, Excitatory Amino Acid Antagonists pharmacology, Fear drug effects, Humans, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate metabolism, Reflex, Startle drug effects, Structure-Activity Relationship, Anti-Anxiety Agents chemical synthesis, Excitatory Amino Acid Antagonists chemical synthesis, Receptors, Metabotropic Glutamate antagonists & inhibitors
- Abstract
2-Methyl-6-(phenylethynyl)pyridine (3), a potent noncompetitive mGlu5 receptor antagonist widely used to characterize the pharmacology of mGlu5 receptors, suffers from a number of shortcomings as a therapeutic agent, including off-target activity and poor aqueous solubility. Seeking to improve the properties of 3 led to the synthesis of compound 9, a highly selective mGlu5 receptor antagonist that is 5-fold more potent than 3 in the rat fear-potentiated startle model of anxiety.
- Published
- 2003
- Full Text
- View/download PDF
63. [3H]Methoxymethyl-3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine binding to metabotropic glutamate receptor subtype 5 in rodent brain: in vitro and in vivo characterization.
- Author
-
Anderson JJ, Rao SP, Rowe B, Giracello DR, Holtz G, Chapman DF, Tehrani L, Bradbury MJ, Cosford ND, and Varney MA
- Subjects
- Animals, Binding Sites physiology, Cerebellum metabolism, Excitatory Amino Acid Antagonists chemistry, Excitatory Amino Acid Antagonists metabolism, Hippocampus metabolism, Male, Pyridines chemistry, Rats, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Thiazoles chemistry, Brain metabolism, Pyridines metabolism, Receptors, Metabotropic Glutamate antagonists & inhibitors, Receptors, Metabotropic Glutamate metabolism, Thiazoles metabolism
- Abstract
The binding of [3H]methoxymethyl-3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (methoxymethyl-MTEP), a potent and selective antagonist for metabotropic glutamate (mGlu)5 receptors, was characterized in rat brain both in vitro and in vivo. Nonspecific binding, as defined with 10 microM 2-methyl-6-(phenylethynyl)-pyridine (MPEP), was less than 10% of total binding in rat brain membranes. The binding of [3H]methoxymethyl-MTEP was of high affinity (K(d) = 20 +/- 2.7 nM), saturable (B(max) = 487 +/- 48 fmol/mg protein), and to a single site. The mGlu5 antagonists methoxymethyl-MTEP and MPEP displaced [3H]methoxymethyl-MTEP binding with IC50 values of 30 and 15 nM, respectively. In vivo administration of [3H]methoxymethyl-MTEP (50 microCi/kg i.v.) revealed 12-fold higher binding in hippocampus (an area enriched in mGlu5 receptors) relative to cerebellum (an area with few mGlu5 receptors) in rats. Similarly, administration of [3H]methoxymethyl-MTEP to mGlu5-deficient mice demonstrated binding at background levels in forebrain, whereas wild-type littermates exhibited 17-fold higher binding in forebrain relative to cerebellum. Systemic administration of unlabeled mGlu5 antagonists methoxymethyl-MTEP and MPEP to rats reduced the binding of [3H]methoxymethyl-MTEP with ID50 values of 0.8 and 2 mg/kg i.p., respectively, 1 h post-treatment. The mGlu5 agonist 2-chloro-5-hydroxyphenylglycine (CHPG) (0.3, 1, and 3 micromol) dose-dependently increased phosphoinositide (PI) hydrolysis in the hippocampus after i.c.v. administration in rats. CHPG-evoked increases in PI hydrolysis were blocked with MPEP at a dose (10 mg/kg i.p.) that markedly reduced [3H]methoxymethyl-MTEP binding in vivo. These results indicate that [3H]methoxymethyl-MTEP is a selective radioligand for labeling mGlu5 and is useful for studying the binding of mGlu5 receptors in rat brain in vitro and in vivo.
- Published
- 2002
- Full Text
- View/download PDF
64. One-step synthesis of 3-aryl- and 3,4-diaryl-(1H)-pyrroles using tosylmethyl isocyanide (TOSMIC).
- Author
-
Smith ND, Huang D, and Cosford ND
- Subjects
- Molecular Structure, Cyanides chemistry, Porphyrins chemical synthesis, Porphyrins chemistry, Pyrroles chemical synthesis, Pyrroles chemistry
- Abstract
A one-step synthesis of 3-aryl and 3,4-diaryl-(1H)-pyrroles from TOSMIC and commercially available or readily synthesized arylalkenes is reported. Optimal conditions were found to be NaOtBu in DMSO. The methodology was particularly efficient (yields > 65%) when electron poor aryl groups were attached to the alkene.[ reaction: see text]
- Published
- 2002
- Full Text
- View/download PDF
65. Recent advances in the modulation of voltage-gated ion channels for the treatment of epilepsy.
- Author
-
Cosford ND, Meinke PT, Stauderman KA, and Hess SD
- Subjects
- Animals, Anticonvulsants chemistry, Anticonvulsants therapeutic use, Calcium Channel Blockers chemistry, Calcium Channel Blockers therapeutic use, Epilepsy metabolism, Humans, Potassium Channel Blockers chemistry, Potassium Channel Blockers therapeutic use, Sodium Channel Blockers chemistry, Sodium Channel Blockers therapeutic use, Calcium Channels metabolism, Epilepsy drug therapy, Potassium Channels, Voltage-Gated metabolism, Sodium Channels metabolism
- Abstract
Regardless of the voltage-gated ion channel that is targeted in a drug discovery effort for the treatment of epilepsy, two routes have been followed historically: 1). a compound initially, and often surreptitiously, discovered due to activity in animal seizure models is further optimized by medicinal chemistry, or 2). a molecular target is identified based on the phenotype of transgenic animals, or linkage studies from humans with the disease, and compounds are then investigated within a mechanistic framework. Antagonists of voltage-gated sodium channels have been pursued utilizing primarily the first approach; many of these compounds also have significant activity at other ion channels. Both approaches have been utilized to discover voltage-gated calcium channel antagonists, although most efforts to date have used the first approach. Several spontaneous mutant mice and transgenic animals have been utilized to probe the role of the numerous voltage-gated calcium channel subunits and their isoforms as potential molecular targets. Compounds that open or prolong the opening of voltage-gated potassium channels have been discovered using the first approach, with a detailed understanding of the molecular target and mechanism of action coming to light several years later. Genetic evidence from humans is limited to relatively rare forms of epilepsy, and transgenic animals with interesting phenotypes do not always translate into good molecular targets in humans. No clinically-useful antiepileptic drug (AED) has been developed to date that specifically interacts with one, or even one class, of ion channels to produce a therapeutic effect. The tools now exist to search for potent, selective, and safe ion channel modulators for the treatment of epilepsy. This review seeks to summarize the most recent pre-clinical and clinical efforts focused on voltage-gated ion-channels for the development of AEDs.
- Published
- 2002
- Full Text
- View/download PDF
66. Recombinant human receptors and functional assays in the discovery of altinicline (SIB-1508Y), a novel acetylcholine-gated ion channel (nAChR) agonist.
- Author
-
Cosford ND, Bleicher L, Vernier JM, Chavez-Noriega L, Rao TS, Siegel RS, Suto C, Washburn M, Lloyd GK, and McDonald IA
- Subjects
- Calcium metabolism, Dopamine metabolism, Humans, Ion Channel Gating drug effects, Ion Channels drug effects, Receptors, Cholinergic chemistry, Recombinant Proteins, Ion Channels metabolism, Nicotinic Agonists pharmacology, Pyridines pharmacology, Pyrrolidines pharmacology, Receptors, Cholinergic drug effects
- Abstract
Neuronal nicotinic acetylcholine receptors (nAChRs) are a class of ion channels with significant potential as molecular targets for the design of drugs to treat a variety of CNS disorders. The discovery that neuronal nAChRs are further subdivided into multiple subtypes suggests that drugs which act selectively at specific nAChR subtypes might effectively treat Parkinson's disease (PD), Alzheimer's disease (AD), schizophrenia, ADHD, depression, anxiety or pain without the accompanying adverse side effects associated with non-selective agents such as nicotine (1) and epibatidine. Altinicline (SIB-1508Y) is a novel, small molecule designed to selectively activate neuronal nAChRs and is undergoing clinical evaluation for the treatment of PD. It was selected from a series of compounds primarily on the basis of results from functional assays, including (a) measurement of Ca2+ flux in stable cell lines expressing specific recombinant human neuronal nAChR subtypes; (b) determination of in vitro and in vivo neurotransmitter release; (c) in vivo models of PD. Biological data on both altinicline and the series of compounds from which it was selected are reported.
- Published
- 2000
- Full Text
- View/download PDF
67. SIB-1757 and SIB-1893: selective, noncompetitive antagonists of metabotropic glutamate receptor type 5.
- Author
-
Varney MA, Cosford ND, Jachec C, Rao SP, Sacaan A, Lin FF, Bleicher L, Santori EM, Flor PJ, Allgeier H, Gasparini F, Kuhn R, Hess SD, Veliçelebi G, and Johnson EC
- Subjects
- Animals, Animals, Newborn, Binding, Competitive, Brain cytology, Brain drug effects, Brain metabolism, CHO Cells, Calcium metabolism, Cells, Cultured, Cricetinae, Excitatory Amino Acid Antagonists chemistry, Humans, In Vitro Techniques, Inositol Phosphates metabolism, Methoxyhydroxyphenylglycol analogs & derivatives, Methoxyhydroxyphenylglycol antagonists & inhibitors, Neurons drug effects, Phenazopyridine chemistry, Phenazopyridine pharmacology, Pyridines chemistry, Rats, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Recombinant Proteins metabolism, Structure-Activity Relationship, Excitatory Amino Acid Antagonists pharmacology, Phenazopyridine analogs & derivatives, Pyridines pharmacology, Receptors, Metabotropic Glutamate antagonists & inhibitors
- Abstract
Cell lines expressing the human metabotropic glutamate receptor subtype 5a (hmGluR5a) and hmGluR1b were used as targets in an automated high-throughput screening (HTS) system that measures changes in intracellular Ca2+ ([Ca2+]i) using fluorescence detection. This functional screen was used to identify the mGluR5-selective antagonist, SIB-1757 [6-methyl-2-(phenylazo)-3-pyridinol], which inhibited the glutamate-induced [Ca2+]i responses at hmGluR5 with an IC50 of 0.37 microM compared with an IC50 of >100 microM at hmGluR1. Schild analysis demonstrated a noncompetitive mechanism of inhibition. Pharmacophore mapping was used to identify an additional compound, SIB-1893 [(E)-2-methyl-6-(2-phenylethenyl)pyridine], which was also shown to block glutamate-induced increases in [Ca2+]i at hmGluR5 with an IC50 of 0.29 microM compared with an IC50 of >100 microM at hmGluR1. SIB-1757 and SIB-1893 showed little or no activity when tested for agonist and antagonist activity at the other recombinant human mGluR subtypes, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and N-methyl-D-aspartate receptors. In rat neonatal brain slices, SIB-1757 and SIB-1893 inhibited (S)-3,5-dihydroxyphenylglycine (DHPG)-evoked inositol phosphate accumulation in hippocampus and striatum by 60% to 80%, with a potency similar to that observed on recombinant mGluR5. However, in the cerebellum, a brain region with low mGluR5 expression, SIB-1757 failed to inhibit DHPG-evoked inositol phosphate accumulation. In cultured rat cortical neurons, SIB-1757 and SIB-1893 largely inhibited DHPG-evoked [Ca2+]i signals, revealing a population of neurons that were less sensitive to SIB-1757 and SIB-1893. This is the first description of highly selective, noncompetitive mGluR5 antagonists. These compounds will be useful tools in evaluating the role of mGluR5 in normal physiology and in animal models of disease.
- Published
- 1999
68. 4-[[2-(1-Methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB-1553A): a novel cognitive enhancer with selectivity for neuronal nicotinic acetylcholine receptors.
- Author
-
Vernier JM, El-Abdellaoui H, Holsenback H, Cosford ND, Bleicher L, Barker G, Bontempi B, Chavez-Noriega L, Menzaghi F, Rao TS, Reid R, Sacaan AI, Suto C, Washburn M, Lloyd GK, and McDonald IA
- Subjects
- Animals, Binding, Competitive, Cell Line, Cerebral Cortex metabolism, Humans, In Vitro Techniques, Nicotinic Agonists metabolism, Nicotinic Agonists pharmacology, Nootropic Agents metabolism, Nootropic Agents pharmacology, Oocytes, Patch-Clamp Techniques, Phenols metabolism, Phenols pharmacology, Pyrrolidines metabolism, Pyrrolidines pharmacology, Rats, Rats, Sprague-Dawley, Transfection, Xenopus, Neurons metabolism, Nicotinic Agonists chemical synthesis, Nootropic Agents chemical synthesis, Phenols chemical synthesis, Pyrrolidines chemical synthesis, Receptors, Nicotinic metabolism
- Published
- 1999
- Full Text
- View/download PDF
69. Conformationally restricted analogues of nicotine and anabasine.
- Author
-
Vernier JM, Holsenback H, Cosford ND, Whitten JP, Menzaghi F, Reid R, Rao TS, Sacaan AI, Lloyd GK, Suto CM, Chavez-Noriega LE, Washburn MS, Urrutia A, and McDonald IA
- Subjects
- Anabasine chemical synthesis, Anabasine pharmacology, Animals, Antiparkinson Agents chemical synthesis, Antiparkinson Agents chemistry, Antiparkinson Agents pharmacology, Calcium metabolism, Cell Line, Cholinergic Agonists chemistry, Cholinergic Agonists pharmacology, Drug Design, Humans, Macromolecular Substances, Molecular Conformation, Nicotine chemical synthesis, Nicotine pharmacology, Parkinson Disease, Secondary drug therapy, Piperidines chemistry, Piperidines pharmacology, Pyridines chemistry, Pyridines pharmacology, Recombinant Proteins drug effects, Structure-Activity Relationship, Transfection, Anabasine analogs & derivatives, Anabasine chemistry, Cholinergic Agonists chemical synthesis, Neurons metabolism, Nicotine analogs & derivatives, Nicotine chemistry, Piperidines chemical synthesis, Pyridines chemical synthesis
- Abstract
A series of conformationally restricted analogues of nicotine has been synthesized and evaluated as agonists of neuronal acetylcholine receptors. Compound 2 (SIB-1663), which selectively activated human recombinant alpha 2 beta 4 and alpha 4 beta 4 nAChRs, was shown to be active in animal models of Parkinson's disease and pain.
- Published
- 1998
- Full Text
- View/download PDF
70. The potential of subtype-selective neuronal nicotinic acetylcholine receptor agonists as therapeutic agents.
- Author
-
Lloyd GK, Menzaghi F, Bontempi B, Suto C, Siegel R, Akong M, Stauderman K, Velicelebi G, Johnson E, Harpold MM, Rao TS, Sacaan AI, Chavez-Noriega LE, Washburn MS, Vernier JM, Cosford ND, and McDonald LA
- Subjects
- Animals, Humans, Neurons drug effects, Receptors, Nicotinic metabolism, Receptors, Nicotinic physiology, Substrate Specificity, Neurons ultrastructure, Nicotinic Agonists pharmacology, Receptors, Nicotinic drug effects
- Abstract
Neuronal nicotinic acetylcholine receptors (NAChRs) are pentameric ligand-gated ion channel receptors which exist as different functional subunit combinations which apparently subserve different physiological functions as indicated by molecular biological and pharmacological techniques. It is possible to design and synthesize novel compounds that have greater selective affinities and efficacies than nicotine for different NAChRs, which should translate into different behavioral profiles and therapeutic potentials. Examples of NAChR agonists studied are nicotine, SIB-1508Y, SIB-1553A and epibatidine. These compounds have different degrees of selectivity for human recombinant NAChRs, different neurotransmitter release profiles in vitro and in vivo and differential behavioral profiles. Preclinical studies suggest that SIB-1508Y is a candidate for the treatment of the motor and cognitive deficits of Parkinson's disease, whereas SIB-1553A appears to have potential as a candidate for the treatment of Alzheimer's disease. Epibatidine has a strong analgesic profile, however the ratio between pharmacological activity and undesirable effects is so low that it is difficult to envisage the use of this compound therapeutically. Nicotine has a broad profile of pharmacological activity, for instance demonstrating activity in models for cognition and analgesia. As for epibatidine, the adverse effects of nicotine severely limits its therapeutic use in humans. The discovery of subtype-selective NAChR agonists such as SIB-1508Y and SIB-1553A provides a new class of neuropsychopharmacological agents with better therapeutic ratios than nonspecific agents such as nicotine.
- Published
- 1998
- Full Text
- View/download PDF
71. Pharmacological characterization of SIB-1765F: a novel cholinergic ion channel agonist.
- Author
-
Sacaan AI, Reid RT, Santori EM, Adams P, Correa LD, Mahaffy LS, Bleicher L, Cosford ND, Stauderman KA, McDonald IA, Rao TS, and Lloyd GK
- Subjects
- Animals, Calcium metabolism, Corpus Striatum metabolism, Dopamine metabolism, Male, Microdialysis, Norepinephrine metabolism, Olfactory Pathways metabolism, Radioligand Assay, Rats, Rats, Sprague-Dawley, Receptors, Nicotinic metabolism, Ion Channels agonists, Nicotinic Agonists pharmacology, Pyridines pharmacology, Pyrrolidines pharmacology
- Abstract
Nicotine, the prototypical agonist for neuronal nicotinic acetylcholine receptors (NAChR), nonselectively activates NAChR limiting its use in elucidating the function of NAChR subtypes. SIB-1765F is a subtype selective NAChR agonist that displaces [3H]-nicotine binding with an IC50 of 4.6 nM and [3H]-cytisine binding with an IC50 of 12.2 nM which is 2000- to 6000-fold lower than its displacement of [3H]-QNB or [125I]-alpha-bungarotoxin. SIB-1765F did not inhibit human or rat cholinesterases or the uptake of [3H]-DA in synaptosomal preparations. SIB-1765F mimicked (-)-nicotine in stimulating [3H]-DA release from rat striatal and olfactory tubercle slices, with EC50 values of 99.6 and 39.6 microM, respectively. Such stimulation was sensitive to mecamylamine and DH beta E. SIB-1765F also released endogenous DA in the striatum and the nucleus accumbens as measured by in vivo microdialysis. SIB-1765F was less efficacious than (-)-nicotine at stimulating [3H]-NE release from rat hippocampal slices; in contrast, SIB-1765F increased [3H]-NE release from rat thalamic and cortical slices with efficacies approaching those of (-)-nicotine. Similar to (-)-nicotine and (+/-)-epibatidine, subcutaneous administration of SIB-1765F increased the turnover rate of dopamine ex vivo both in the striatum and olfactory tubercles in a mecamylamine-sensitive manner. Because the release of striatal DA and hippocampal NE appears to be regulated by distinct NAChR, differential effects of SIB-1765F on striatal DA and hippocampal NE release supports the NAChR subtype selectivity of SIB-1765F compared to (-)-nicotine. This is further demonstrated by observations showing that SIB-1765F has a higher affinity for h alpha 4 beta 2 NAChR relative to h alpha 4 beta 4 NAChRs in displacing [3H]-epibatidine binding and increasing cytosolic CA+2 concentration in cell lines stably expressing h alpha 4 beta 2 or h alpha 4 beta 4.
- Published
- 1997
72. (S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate (SIB-1508Y): a novel anti-parkinsonian agent with selectivity for neuronal nicotinic acetylcholine receptors.
- Author
-
Cosford ND, Bleicher L, Herbaut A, McCallum JS, Vernier JM, Dawson H, Whitten JP, Adams P, Chavez-Noriega L, Correa LD, Crona JH, Mahaffy LS, Menzaghi F, Rao TS, Reid R, Sacaan AI, Santori E, Stauderman KA, Whelan K, Lloyd GK, and McDonald IA
- Subjects
- Animals, Antiparkinson Agents chemistry, Cell Line, Female, Humans, Kinetics, Molecular Structure, Oocytes physiology, Patch-Clamp Techniques, Pyridines chemistry, Pyrrolidines chemistry, Receptors, Nicotinic drug effects, Recombinant Proteins drug effects, Recombinant Proteins metabolism, Stereoisomerism, Xenopus, Antiparkinson Agents chemical synthesis, Antiparkinson Agents pharmacology, Neurons physiology, Pyridines chemical synthesis, Pyridines pharmacology, Pyrrolidines chemical synthesis, Pyrrolidines pharmacology, Receptors, Nicotinic physiology
- Published
- 1996
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.