title: SB-236057, a selective 5-HT1B receptor inverse agonist, blocks the 5-HT human terminal autoreceptor.
abstract: A novel compound, SB-236057 (1'-ethyl-5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl- 4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperid ine]) has been shown to have high affinity for human 5-hydroxytryptamine1B (5-HT1B) receptors (pKi = 8.2) and displays over 75 or more-fold selectivity for the human 5-HT1B receptor over other 5-HT receptors, including the human 5-HT1D receptor, and a range of other receptors, ion channels and enzymes. In functional studies using [35S]GTPgammaS binding, SB-236057 displayed negative intrinsic activity (pEC50 = 8.0) at human 5-HT1B receptors stably expressed in Chinese Hamster Ovary (CHO) cells and caused a rightward shift of agonist concentration response curves consistent with competitive antagonism (pA2 = 8.9). SB-236057 potentiated [3H]5-HT release from electrically stimulated guinea pig or human cortical slices. SB-236057 also abolished the inhibitory effect of exogenously superfused 5-HT on electrically-stimulated release from slices of the guinea pig cortex. These studies using SB-236057 confirm that, in both the guinea pig and human cerebral cortex, the terminal 5-HT autoreceptor is of the 5-HT1B subtype.
authors.affiliation: Department of Neurosciences, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK.
authors.forename: D N
authors.initials: DN
authors.lastname: Middlemiss
authors.forename: M
authors.initials: M
authors.lastname: Göthert
authors.forename: E
authors.initials: E
authors.lastname: Schlicker
authors.forename: C M
authors.initials: CM
authors.lastname: Scott
authors.forename: J V
authors.initials: JV
authors.lastname: Selkirk
authors.forename: J
authors.initials: J
authors.lastname: Watson
authors.forename: L M
authors.initials: LM
authors.lastname: Gaster
authors.forename: P
authors.initials: P
authors.lastname: Wyman
authors.forename: G
authors.initials: G
authors.lastname: Riley
authors.forename: G W
authors.initials: GW
authors.lastname: Price
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000187:drug effects*; D001665:Binding Sites; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism*; D006224:Cricetinae; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000145:classification* / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D017660:Autoreceptors; D007211:Indoles; D011725:Pyridines; D011985:Receptors, Serotonin; C121558:SB 236057; D012702:Serotonin Antagonists; D012701:Serotonin