title: Selectivity for omega-receptor subtypes as a strategy for the development of anxiolytic drugs.
abstract: The names omega 1-, omega 2-, and omega 3-receptor subtypes have recently been proposed to replace the nomenclature of BZ1, BZ2 and BZp receptors in order to avoid a nomenclature exclusively linked to the benzodiazepine (BZ) structure or to a regional localization. The multiplicity of pharmacological actions of currently available anxiolytics may be due to their lack of selectivity for omega-receptor subtypes. The idea that a receptor-subtype selective drug will offer a more specific therapeutic profile is widely accepted. In the field of preferential anxiolytic or hypnotic drugs, imidazopyridines represent a new chemical and therapeutic class possessing selectivity for omega-receptor subtypes. Of these, alpidem (6-chloro-2-(4-chloro-phenyl)-N,N-dipropylimid-azo[1,2-a] pyridine-3-acetamide) behaves preferentially as an anxiolytic drug in both animal models and man. Receptor-binding studies using alpidem either as a displacer or as a radioligand indicate that the compound has a high affinity for omega 1- and for omega 3- but not for omega 2-receptors. In the human brain, the binding of [3H]-alpidem to omega 1- and omega 3-receptors occurs with a Kd of 1.67 nM and 0.33 nM respectively. The binding of [3H]-alpidem to omega 1-receptors in the rat cerebral cortex with a Kd of 1.5 nM is enhanced by GABA, and in contrast to anxiolytics of the benzodiazepine type, is unaffected by chloride ions and pentobarbital. In conclusion, the affinity of alpidem for the omega 1-receptor is allosterically influenced by the activation of the GABAA receptor but not by other components of the same receptor complex.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Biology, Synthélabo Recherche, Paris, France.
authors.forename: S Z
authors.initials: SZ
authors.lastname: Langer
authors.forename: S
authors.initials: S
authors.lastname: Arbilla
authors.forename: S
authors.initials: S
authors.lastname: Tan
authors.forename: K G
authors.initials: KG
authors.lastname: Lloyd
authors.forename: P
authors.initials: P
authors.lastname: George
authors.forename: J
authors.initials: J
authors.lastname: Allen
authors.forename: A E
authors.initials: AE
authors.lastname: Wick
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D011963:Receptors, GABA-A / Q000145:classification / Q000502:physiology*
chemical_list: D014151:Anti-Anxiety Agents; D011963:Receptors, GABA-A