SB-236057, a selective 5-HT1B receptor inverse agonist, blocks the 5-HT human terminal autoreceptor.

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.