Binding affinity of sarpogrelate, a new antiplatelet agent, and its metabolite for serotonin receptor subtypes

We analyzed the displacement activity of sarpogrelate and its active metabolite (M-l) in the radiolabeled ligand binding to various 5-hydroxytryptamine (5-HT) receptor subtypes using rat brain cortical membranes. Sarpogrelate was shown to have the same affinity as ritanserin for 5-HT2A receptors, with a K-i value of 8.39 nM. The active metabolite of sarpogrelate, M-l, was more active than sarpogrelate itself and of ritanserin, with a K-i value of 1.70 nM. Both sarpogrelate and M-l had no affinity for 5-HT1A receptors, but these substances, at a concentration of 10 mu M, displaced the specific binding to the 5-HT1B receptors of [I-125] iodocyanopindolol, resulting in K-i values of 0.881 and 0.859 mu M, respectively. The K-i values of sarpogrelate and M-I are almost the same as that of ritanserin, a specific 5-HT2 receptor antagonist. Sarpogrelate and M-l, as well as ritanserin, are shown to have very low affinity for 5-HT1B receptors. Both sarpogrelate and M-l had no affinity for 5-HT3 receptor subtypes. In the 5-HT4 receptor binding experiments, sarpogrelate exhibited almost no affinity, while M-l, at the concentration of 10 mu M, displaced the binding activity, resulting in a K-i value of 0.838 mu M. Both drugs had a weak antagonistic effect on a 5-HT4 receptor-mediated function, i.e., the 5-HT-induced relaxation of rat isolated esophageal tunica muscularis mucosae. In conclusion, sarpogrelate and M-l have high affinity for 5-HT2A receptors with a relatively high selectivity.