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-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.
Nishio
H
H
Department of Pharmacology, Hiroshima University School of Medicine, Japan.
Inoue
A
A
Nakata
Y
Y
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol; D007553:Isotope Labeling; D007650:Ketanserin / Q000378:metabolism; D007928:Lethal Dose 50; D008297:Male; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D011412:Propanolamines / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D016713:Ritanserin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000378:metabolism*; D013386:Succinates / Q000378:metabolism*; D000077526:Tropisetron
D007093:Imidazoles; D007211:Indoles; D007457:Iodine Radioisotopes; D010879:Piperazines; D011412:Propanolamines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013386:Succinates; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; C059068:GR 65630; C099060:1-(2-(3-methoxyphenyl)ethyl)phenoxy-3-(dimethylamino)-2-propanol; D016713:Ritanserin; C064294:sarpogrelate; D000077526:Tropisetron; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D020120:Iodocyanopindolol; D007650:Ketanserin; D010869:Pindolol