Abstract
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 (p K 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 1 2 receptor antagonist, methiothepin, exhibited similar binding affinities (p K 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 p K b values determined in functional assays closely matched their p K 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.
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