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

Department of Pharmacology, Hiroshima University School of Medicine, Japan.

We analyzed the displacement activity of sarpogrelate and its active metabolite (M-1) 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 Ki value of 8.39 nM. The active metabolite of sarpogrelate, M-1, was more active than sarpogrelate itself and of ritanserin, with a Ki value of 1.70 nM. Both sarpogrelate and M-1 had no affinity for 5-HT1A receptors, but these substances, at a concentration of 10 microM, displaced the specific binding to the 5-HT1B receptors of [125I]iodocyanopindolol, resulting in Ki values of 0.881 and 0.859 microM, respectively. The Ki values of sarpogrelate and M-1 are almost the same as that of ritanserin, a specific 5-HT2 receptor antagonist. Sarpogrelate and M-1, as well as ritanserin, are shown to have very low affinity for 5-HT1B receptors. Both sarpogrelate and M-1 had no affinity for 5-HT3 receptor subtypes. In the 5-HT4 receptor binding experiments, sarpogrelate exhibited almost no affinity, while M-1, at the concentration of 10 microM, displaced the binding activity, resulting in a Ki value of 0.838 microM. 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-1 have high affinity for 5-HT2A receptors with a relatively high selectivity.

PMID: 8937629 [PubMed - indexed for MEDLINE]