SB‐224289–a novel selective (human) 5‐HT 1B receptor antagonist with negative intrinsic activity

1 Human 5‐HT 1B (h5‐HT 1B ) and human 5‐HT 1D (h5‐HT 1D ) receptors show remarkably similar pharmacology with few compounds discriminating the receptors. We report here on a novel compound, SB‐224289 (1′‐Methyl‐5‐[[2′‐methyl‐4′‐(5‐methyl‐1,2,4‐oxadiazol‐3‐yl)biphenyl‐4‐yl]carbonyl]‐2,3,6,7‐tetrahydrospiro [furo [2,3‐f]indole‐3,4′‐piperidine] oxalate), which has high affinity for h5‐HT 1B receptors (pK 1 =8.16±0.06) and displays over 75 fold selectivity for the h5‐HT 1B receptor over all other 5‐HT receptors including the h5‐HT 1D receptor and all other receptors tested thus far. 2 Functional activity of SB‐224289 was measured in a [ 35 S]GTPγS binding assay on recombinant h5‐HT 1B and h5‐HT 1D receptors expressed in Chinese Hamster Ovary (CHO) cells. SB‐224289 displayed negative intrinsic activity at both receptors with higher potency at h5‐HT 1B 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 [ 3 H]5‐HT release from electrically stimulated guinea‐pig cerebral cortical slices to the same extent as as the non‐selective 5‐HT 1 antagonist methiothepin. SB‐224289 also fully reversed the inhibitory effect of exogenously superfused 5‐HT on electrically stimulated release. 4 Using SB‐224289 as a tool compound, we confirm that in guinea‐pig cerebral cortex the terminal 5‐HT autoreceptor is of the 5‐HT 1B subtype.British Journal of Pharmacology (1998) 125 , 202–208; doi: 10.1038/sj.bjp.0702059