SB-224289 -: a novel selective (human) 5-HT1B receptor antagonist with negative intrinsic activity

1 Human 5-HT1B (h(5)-HT1B) and human 5-HT1D (h(5)-HT1D) receptors show remarkably similar pharmacology with few compounds discriminating the receptors. We report here on a novel compound, SE-224289 (1'-Methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]2,3,6,7-tetra-, hydrospiro [furo [2,3-f]indole-3,4'-piperidine] oxalate), which has high affinity for h5-HT1B receptors (pK(1) = 8.16 +/- 0.06) and displays over 75 fold selectivity for the h(5)-HT1B receptor over all other 5-HT receptors including the h5-HT1D receptor and all other receptors tested thus far. 2 Functional activity of SE-224289 was measured in a [S-35]GTP gamma S binding assay on recombinant h5-HT1B and h5-HT1D receptors expressed in Chinese Hamster Ovary (CHO) cells. SE-224289 displayed negative intrinsic activity at both receptors with higher potency at h5-HT1B receptors. SB-224289 caused a rightward shift of agonist concentration response curves consistent with competitive antagonism and generated affinities comparable with those obtained from competition radioligand receptor binding studies. 3 SB-224289 potentiated [H-3]5-HT release from electrically stimulated guinea-pig cerebral cortical slices to the same extent as as the non-selective 5-HT1 antagonist methiothepin. SE-234289 also fully reversed the inhibitory effect of exogenously superfused 5-HT on electrically stimulated release. 4 Using SE-224289 as a tool compound, we confirm that in guinea-pig cerebral cortex the terminal 5-HT autoreceptor is of the 5-HT1B subtype.