title: GR127935: a potent and selective 5-HT1D receptor antagonist.
abstract: GR127935 is the most potent 5-HT1D receptor antagonist yet described, possessing nanomolar affinity at human 5-HT1D receptors. Sumatriptan-induced contractions of the dog isolated basilar artery and saphenous vein are antagonised by GR127935 in an insurmountable manner indicative of its slow dissociation from the 5-HT1D receptor. 5-HT1D receptor-mediated hypothermia and rotational behaviour in guinea-pigs are antagonised potently, and with long duration, by GR127935, administered by a variety of routes. GR127935 also blocks central 5-HT1D autoreceptors in vitro and in vivo. GR127935 has much lower affinity at other 5-HT, and non-5-HT, receptors. In functional studies, GR127935 fails to affect 5-HT2 receptor-mediated 'wet dog shakes' in guinea-pigs and 5-HT1A receptor-mediated inhibition of 5-HT release in rat dorsal raphé nucleus. The compound has a good safety profile in all species tested. It is concluded that GR127935 is a useful pharmacological tool to characterise 5-HT1D receptor function.
authors.affiliation: Glaxo Research and Development Ltd., Herts, UK.
authors.forename: M
authors.initials: M
authors.lastname: Skingle
authors.forename: D T
authors.initials: DT
authors.lastname: Beattie
authors.forename: D I
authors.initials: DI
authors.lastname: Scopes
authors.forename: S J
authors.initials: SJ
authors.lastname: Starkey
authors.forename: H E
authors.initials: HE
authors.lastname: Connor
authors.forename: W
authors.initials: W
authors.lastname: Feniuk
authors.forename: M B
authors.initials: MB
authors.lastname: Tyers
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D010069:Oxadiazoles / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D010069:Oxadiazoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C090701:GR 127935