Biochemical, electrophysiological and neurohormonal studies with B-20991, a selective 5-HT1A receptor agonist

Different receptor subtypes mediate the effects produced by serotonin (5-HT ) in mammals. Besides their proved anxiolytic action, agonists of the 5-HT1 A receptor subtype show prospects as antidepressants or neuroprotective age nts in case of ischemia. In order to better define the pharmacological prof ile and determine the selectivity for the 5-HT receptor type, the propertie s of the new 5-HT1A receptor agonist 2[[4-(o-methoxyphenyl)piperazin-1-yl]- methyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine (B 20991), an arylpiperazin e derivative, have now been further studied. B-20991 was found to antagoniz e the forskolin-induced increase of cAMP synthesis in a HeLa cell line tran sfected with the human 5-HT1A in a process sensitive to the selective block er N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridiny-cyclohexanec arboxamide maleate (WAY 100635). Additionally, B-20991 showed a dose-depend ent inhibition of the spontaneous on-going activity of serotonin (5-HT) neu rons in the dorsal raphe nucleus in rats, an effect that was reversed by tr eatment with WAY 100635. This, together with the fact that the hypothermia induced by B-20991 in mice was also antagonized by WAY 100635, suggests tha t the new compound acts upon somatodendritic 5-HT1A receptors. Additional a ctivation of 5-HT1A postsynaptic receptors was indicated by the increase of corticosterone plasma levels induced by B-20991 in the rat. These results demonstrate that B-20991 is a selective 5-HT1A receptor agonist acting both pre- and postsynaptically, which represents an useful pharmacological tool to study 5-HT1A-receptor-mediated effects. Copyright (C) 2001 S. Karger AG , Basel.