SB-224289 - A NOVEL SELECTIVE (HUMAN) 5-HT1B RECEPTOR ANTAGONIST WITHNEGATIVE 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 diazol-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 recepto rs (pK(1) = 8.16 +/- 0.06) and displays over 75 fold selectivity for t he h(5)-HT1B receptor over all other 5-HT receptors including the h5-H T1D receptor and all other receptors tested thus far. 2 Functional act ivity of SE-224289 was measured in a [S-35]GTP gamma S binding assay o n recombinant h5-HT1B and h5-HT1D receptors expressed in Chinese Hamst er 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 cons istent with competitive antagonism and generated affinities comparable with those obtained from competition radioligand receptor binding stu dies. 3 SB-224289 potentiated [H-3]5-HT release from electrically stim ulated guinea-pig cerebral cortical slices to the same extent as as th e non-selective 5-HT1 antagonist methiothepin. SE-234289 also fully re versed the inhibitory effect of exogenously superfused 5-HT on electri cally stimulated release. 4 Using SE-224289 as a tool compound, we con firm that in guinea-pig cerebral cortex the terminal 5-HT autoreceptor is of the 5-HT1B subtype.