2001 Fiscal Year Final Research Report Summary
Molecular basis of prostanoid receptor-mediated pathogenesis and its drug application
| Project/Area Number |
12557211
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Biological pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
ICHIKAWA Atsushi Kyoto Univ., Grad. Sch. of Pharmaceu. Sci., Professor, 薬学研究科, 教授 (10025695)
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| Co-Investigator(Kenkyū-buntansha) |
MARUYAMA Takayuki Ono Phamaceu. Co. Ltd., Discovery Research Labs.l, Researcher, 創薬第1研, 研究員
HAMANAKA Nobuyuki Ono Phamaceu. Co. Ltd., Dept. of Med. Chem., Principal Researcher, 薬化学研, 研究員
SUMGIMOTO Yukihiko Kyoto Univ., Grad. Sch. of Pharmaceu. Sci., Associate Professor, 薬学研究科, 助教授 (80243038)
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| Project Period (FY) |
2000 – 2001
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| Keywords | prostaglandin / receptor subtypes / signal transduction / gene targeting / cycloxygenase-2 / colon cancer / colitis / receptor blocker |
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| Research Abstract |
Results obtained by Kyoto University Group
(1) Elucidation of patho-physiological roles of prostanoids by using each receptor-deficient mice :
We found that EP2 deficiency attenuated intestinal polyp formation both in number and size in-Apc KO mice. We also showed acceleration of COX-2, EP2 and VEGF expression in the intestinal polyps of wild-type mice, but faint expression of COX-2 or VEGF in those of EP2 and Ape double-knockout mice, suggesting that there exists positive feedback regulation between COX-2 and EP2. We introduced dextransulfate (DSS)-induced colitis model into EP-deficient mice. As a result, only EP4-deficient mice showed severe colitis upon 3%DSS treatment that did not induce significant colitisin wild-type mice. EP4 has been shown to promote epithelial regeneration and to inhibit activation of leukocytes and lymphocytes.
(2) The new signal transduction pathway exerted by prostanoid receptor EP3 :
EP3 has been shown to be coupled to Gi activity, inhibition of adenylate cyc
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lase. EP3 has multiple isoforms that are different in their C-terminal structure and in their agonist-dependent Gi activity. We found that EP3 receptors expressed in COS-7 cells showed augmentation of other receptor-stimulated Gs activity in an agonist-dependent manner. The superactivation of Gs by EP3 receptors was not affected by the treatment of pertussis toxin, suggesting that the superactivation is not Gi-mediated. The EP3 agonist-dependent supeactivation of Gs is observed in any type of mouse EP3 receptor isoforms, irrespective of C-termnal structure of EP3 receptor. This EP3 signaling may reflect some aspects of the physiological function of PGE2, such as pain sensation.]
Results obtained by Ono Pharmaceutical Co. Group
(3) Development of EP4 receptor-specific ligands :
Improvement of EP4-receptor selectivity and the agonist activity by introduction of heteroatoms into the alpha chain of PGE1 was investigated. Of the compounds produced, 16-phenyl-omega-tetranor-3,7-dithiaPGE1 possessing moderate EP4-receptor selectivity and agonist activity, was identified as a new chemical lead for further optimization by modification of the aromatic moiety Based on the information, we also successfully generated an EP4-specific antagonist with a high selectivity. Less
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