RRC ID 6520
著者 Muntasir HA, Bhuiyan MA, Ishiguro M, Ozaki M, Nagatomo T.
タイトル Inverse agonist activity of sarpogrelate, a selective 5-HT2A-receptor antagonist, at the constitutively active human 5-HT2A receptor.
ジャーナル J Pharmacol Sci
Abstract Mutations producing constitutively active G-protein coupled receptors have been found in the pathophysiology of several diseases, implying that inverse agonists at the constitutively active receptors may have preferred therapeutic applications. Because of the involvement of 5-HT(2A) receptors in mediating many cardiovascular diseases, constitutively active mutants of the 5-HT(2A) receptor may be responsible for the disease states. Thus, the purpose of the present study was to investigate the inverse agonist activity of sarpogrelate, a selective 5-HT(2A)-receptor antagonist, and its active metabolite, M-1; and we compared their activities with those of other 5-HT(2A)-receptor antagonists such as ritanserin, ketanserin, and cyproheptadine. Using a constitutively active mutant (C322K) of the human 5-HT(2A) receptor, we demonstrated that like other 5-HT(2A)-receptor antagonists, sarpogrelate acts as a potent inverse agonist by significantly reducing basal inositol phosphate levels. However, there were no significant differences between sarpogrelate and other 5-HT(2A)-receptor antagonists for their inverse agonist activity. Compared with the wild type receptor, mutant receptor displayed significantly higher affinity for 5-HT and lower affinity for sarpogrelate. These results indicate that stabilization of the inactive conformation of the 5-HT(2A) receptor may be a key component of the mechanism of action of sarpogrelate.
巻・号 102(2)
ページ 189-95
公開日 2006-10-1
DOI 10.1254/jphs.fp0060610
PII JST.JSTAGE/jphs/FP0060610
PMID 17031071
MeSH Binding, Competitive Cell Line Cloning, Molecular Dose-Response Relationship, Drug Humans Ligands Mutation* Radioligand Assay Receptor, Serotonin, 5-HT2A* / genetics Serotonin 5-HT2 Receptor Agonists Serotonin 5-HT2 Receptor Antagonists Serotonin Antagonists / metabolism Serotonin Antagonists / pharmacology* Serotonin Receptor Agonists / metabolism Serotonin Receptor Agonists / pharmacology* Succinates / metabolism Succinates / pharmacology* Transfection
IF 2.835
引用数 22
WOS 分野 PHARMACOLOGY & PHARMACY
リソース情報
ヒト・動物細胞