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.

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