3-Heteroaryl-2-pyridones: benzodiazepine site ligands with functional delectivity for alpha 2/alpha 3-subtypes of human GABA(A) receptor-ion channels

Ian Collins; Christopher Moyes; William B Davey; Michael Rowley; Frances A Bromidge; Kathleen Quirk; John R Atack; Ruth M McKernan; Sally-Ann Thompson; Keith Wafford; Gerard R Dawson; Andrew Pike; Bindi Sohal; Nancy N Tsou; Richard G Ball; José L Castro

doi:10.1021/jm0110789

3-Heteroaryl-2-pyridones: benzodiazepine site ligands with functional delectivity for alpha 2/alpha 3-subtypes of human GABA(A) receptor-ion channels

J Med Chem. 2002 Apr 25;45(9):1887-900. doi: 10.1021/jm0110789.

Authors

Ian Collins¹, Christopher Moyes, William B Davey, Michael Rowley, Frances A Bromidge, Kathleen Quirk, John R Atack, Ruth M McKernan, Sally-Ann Thompson, Keith Wafford, Gerard R Dawson, Andrew Pike, Bindi Sohal, Nancy N Tsou, Richard G Ball, José L Castro

Affiliation

¹ Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, CM20 2QR, United Kingdom.

PMID: 11960500
DOI: 10.1021/jm0110789

Abstract

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.

MeSH terms

Animals
Anti-Anxiety Agents / chemical synthesis
Anti-Anxiety Agents / chemistry
Anti-Anxiety Agents / pharmacokinetics
Anti-Anxiety Agents / pharmacology
Anticonvulsants / chemical synthesis
Anticonvulsants / chemistry
Anticonvulsants / pharmacokinetics
Anticonvulsants / pharmacology
Biological Availability
Brain / metabolism
Cell Line
Convulsants / chemical synthesis
Convulsants / chemistry
Convulsants / pharmacokinetics
Convulsants / pharmacology
Crystallography, X-Ray
Epilepsy / drug therapy
GABA Agonists / chemical synthesis
GABA Agonists / chemistry
GABA Agonists / pharmacokinetics
GABA Agonists / pharmacology
Humans
In Vitro Techniques
Ligands
Maze Learning / drug effects
Mice
Oocytes
Patch-Clamp Techniques
Protein Subunits
Pyridones / chemical synthesis*
Pyridones / chemistry
Pyridones / pharmacokinetics
Pyridones / pharmacology
Radioligand Assay
Rats
Receptors, GABA-A / drug effects*
Receptors, GABA-A / metabolism
Receptors, GABA-A / physiology
Structure-Activity Relationship
Xenopus

Substances

Anti-Anxiety Agents
Anticonvulsants
Convulsants
GABA Agonists
Ligands
Protein Subunits
Pyridones
Receptors, GABA-A