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-oxadi azol-2-yl)biphenyl-4-carbonyl)-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3 ,4'-piperidine]) has been shown to have high affinity for human 5-hydroxytr yptamine(1B) (5-HT1B) receptors (pK(i) = 8.2) and displays over 75 or more- fold selectivity for the human 5-HT1B receptor over other 5-HT receptors, i ncluding the human 5-HT1D receptor, and a range of other receptors, ion cha nnels and enzymes. In functional studies using [S-35]GTP gamma S binding, S B-236057 displayed negative intrinsic activity (pEC(50) = 8.0) at human 5-H T1B receptors stably expressed in Chinese Hamster Ovary (CHO) cells and cau sed a rightward shift of agonist concentration response curves consistent w ith competitive antagonism (pA(2) = 8.9). SB-236057 potentiated [H-3]5-HT r elease 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. T hese 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. (C) 1999 Elsevier Science B.V. All rights reserved.