title: Biochemical, electrophysiological and neurohormonal studies with B-20991, a selective 5-HT1A receptor agonist.
abstract: Different receptor subtypes mediate the effects produced by serotonin (5-HT) in mammals. Besides their proved anxiolytic action, agonists of the 5-HT1A receptor subtype show prospects as antidepressants or neuroprotective agents in case of ischemia. In order to better define the pharmacological profile and determine the selectivity for the 5-HT receptor type, the properties 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 arylpiperazine derivative, have now been further studied. B-20991 was found to antagonize the forskolin-induced increase of cAMP synthesis in a HeLa cell line transfected with the human 5-HT1A in a process sensitive to the selective blocker N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY 100635). Additionally, B-20991 showed a dose-dependent inhibition of the spontaneous on-going activity of serotonin (5-HT) neurons in the dorsal raphe nucleus in rats, an effect that was reversed by treatment with WAY 100635. This, together with the fact that the hypothermia induced by B-20991 in mice was also antagonized by WAY 100635, suggests that the new compound acts upon somatodendritic 5-HT1A receptors. Additional activation 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.
authors.affiliation: Unidad de Cartografía Cerebral del Instituto Universitario Pluridisciplinar, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: A G
authors.initials: AG
authors.lastname: Caicoya
authors.forename: M E
authors.initials: ME
authors.lastname: Beneytez
authors.forename: M
authors.initials: M
authors.lastname: Delgado
authors.forename: J
authors.initials: J
authors.lastname: Manzanares
authors.forename: M L
authors.initials: ML
authors.lastname: López-Rodríguez
authors.forename: B
authors.initials: B
authors.lastname: Benhamu
authors.forename: M J
authors.initials: MJ
authors.lastname: Morcillo
authors.forename: M A
authors.initials: MA
authors.lastname: Pozo
authors.forename: F J
authors.initials: FJ
authors.lastname: Rubia
authors.forename: J A
authors.initials: JA
authors.lastname: Fuentes
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002065:Buspirone / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D000242:Cyclic AMP / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: C112914:B 20991; D007093:Imidazoles; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D005576:Colforsin; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D002065:Buspirone; D003345:Corticosterone