3-Heteroaryl-2-pyridones: benzodiazepine site ligands with functional delectivity for alpha 2/alpha 3-subtypes of human GABA(A) receptor-ion channels
| Autor: | Ian Collins, John R. Atack, K Quirk, Bindi Sohal, Andrew Pike, Sally-Ann Thompson, Michael Rowley, Gerard R. Dawson, Richard G. Ball, José L. Castro, Christopher Moyes, William B Davey, Frances A. Bromidge, Keith A. Wafford, Nancy N. Tsou, Ruth M. McKernan |
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| Rok vydání: | 2002 |
| Předmět: |
Patch-Clamp Techniques
Stereochemistry Pyridones Xenopus Alpha (ethology) Biological Availability Convulsants In Vitro Techniques Crystallography X-Ray Ligands Partial agonist Cell Line Mice Radioligand Assay Structure-Activity Relationship Drug Discovery Functional selectivity Inverse agonist Animals Humans Binding site Maze Learning GABA Agonists Binding selectivity Epilepsy GABAA receptor Chemistry Brain Receptors GABA-A Rats Protein Subunits Anxiogenic Anti-Anxiety Agents Oocytes Molecular Medicine Anticonvulsants |
| Zdroj: | Journal of medicinal chemistry. 45(9) |
| ISSN: | 0022-2623 |
| Popis: | A novel series of 3-heteroaryl-5,6-bis(aryl)-1-methyl-2-pyridones were developed with high affinity for the benzodiazepine (BZ) binding site of human gamma-aminobutyric acid (GABA(A)) receptor ion channels, low binding selectivity for alpha 2- and/or alpha 3- over alpha 1-containing GABA(A) receptor subtypes and high binding selectivity over alpha 5 subtypes. High affinity appeared to be associated with a coplanar conformation of the pyridone and sulfur-containing 3-heteroaryl rings resulting from an attractive S.O intramolecular interaction. Functional selectivity (i.e., selective efficacy) for alpha 2 and/or alpha 3 GABA(A) receptor subtypes over alpha1 was observed in several of these compounds in electrophysiological assays. Furthermore, an alpha 3 subtype selective inverse agonist was proconvulsant and anxiogenic in rodents while an alpha 2/alpha 3 subtype selective partial agonist was anticonvulsant and anxiolytic, supporting the hypothesis that subtype selective BZ site agonists may provide new anxiolytic therapies. |
| Databáze: | OpenAIRE |
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