2007 Fiscal Year Final Research Report Summary
Study on the clarification of molecular and pharmacological structure-activity relationships of 5-HT2A antagonists
| Project/Area Number |
17590231
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Nigata University of Phermacy and Applied Life Sciences |
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Principal Investigator |
NAGATOMO Takafumi Nigata University of Phermacy and Applied Life Sciences, Faculty of Pharmaceutical Science, Dept. of Pharmacology, Professor (60121240)
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| Co-Investigator(Kenkyū-buntansha) |
ONUKI Toshio Niigata University of Pharmacy and Applied Life Scienses, Faculty of Pharmaceutical Science Dept. of Pharmacology, Assistant (60288230)
SUGIHARA Takumichi Niigata University of Pharmacy and Applied Life Scienses, Faculty of Pharmaceutical Science Dept. of Organic and Medicinal Chemistry, Professor (40222054)
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| Project Period (FY) |
2005 – 2007
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| Keywords | 5-HT2A receptors / sarpogrelate / modeling / structure-activity relationships / inverse agonist / constitutively active |
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| Research Abstract |
Mutations producing constitutively active G-protein coupled receptors (GPCRs) 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 (IP) 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.
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Research Products
(6 results)
