SB-224289–a novel selective (human) 5-HT_1B receptor antagonist with negative intrinsic activity

Abstract

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 (pK₁=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 [³⁵S]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 [³H]5-HT release from electrically stimulated guinea-pig cerebral cortical slices to the same extent as as the non-selective 5-HT₁ 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.

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