KETANSERIN AND RITANSERIN DISCRIMINATE BETWEEN RECOMBINANT HUMAN 5-HT1D-ALPHA AND 5-HT1D-BETA RECEPTOR SUBTYPES

Compounds able to discriminate functionally between the closely relate d cloned human 5-HT1D alpha and 5-HT1D beta receptor subtypes have not been reported previously. In [H-3]5-HT competition assays, the classi cal 5-HT2A receptor antagonists, ritanserin and ketanserin, displayed moderate affinity (pK(i) = 7.30 and 7.17, respectively) and marked sel ectivity (22-and 71-fold, respectively) for the recombinant human 5-HT 1D alpha subtype relative to the 5-HT1D beta receptor. In contrast, th e nonselective 5-HT1/2 receptor antagonist, methiothepin, exhibited si milar binding affinities (pK(i) = 7.64-8.01) for both recombinant 5-HT 1D subtypes. The antagonistic properties of these compounds were evalu ated for their ability to block 5-HT-induced inhibition of forskolin-s timulated cAMP accumulation in intact cells stably expressing either 5 -HT1D alpha or 5-HT1D beta receptors. All three compounds behaved as a ntagonists devoid of intrinsic activity in the functional assays. The apparent pK(b) values determined in functional assays closely matched their pK(i) values obtained in binding assays. Since ketanserin exhibi ts significant selectivity for the human 5-HT1D alpha receptor, this a ntagonist can be used as a pharmacological tool to discriminate betwee n 5-HT1D alpha and 5-HT1D beta receptor-mediated responses in human ti ssues.