Ketanserin and ritanserin discriminate between recombinant human 5-HT1Dα and 5-HT1Dβ receptor subtypes

Compounds able to discriminate functionally between the closely related cloned human 5-HT_1Dα and 5-HT_1Dβ receptor subtypes have not been reported previously. In [³H]5-HT competition assays, the classical 5-HT_2A receptor antagonists, ritanserin and ketanserin, displayed moderate affinity (pK_i = 7.30 and 7.17, respectively) and marked selectivity (22-and 71-fold, respectively) for the recombinant human 5-HT_1Dα subtype relative to the 5-HT_1Dβ receptor. In contrast, the nonselective 5-HT_{$\text{1}\text{2}$} receptor antagonist, methiothepin, exhibited similar binding affinities (pK_i=7.64−8.01) for both recombinant 5-HT_1D subtypes. The antagonistic properties of these compounds were evaluated for their ability to block 5-HT-induced inhibition of forskolin-stimulated cAMP accumulation in intact cells stably expressing either 5-HT_1Dα or 5-HT_1Dβ receptors. All three compounds behaved as antagonists 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 exhibits significant selectivity for the human 5-HT_1Dα receptor, this antagonist can be used as a pharmacological tool to discriminate between 5-HT_1Dα and 5-HT_1Dβ receptor-mediated responses in human tissues.