| Project/Area Number |
08557134
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (A)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 展開研究 |
|---|
| Research Field |
医薬分子機能学
|
|---|
| Research Institution | HOKKAIDO UNIVERSITY |
|---|
Principal Investigator |
MATSUDA Akira Hokkaido Univ., Fac.of Farm.Sci., Prof., 薬学部, 教授 (90157313)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
YOSHII Kiyonori Kyushu lnst.of Technol., Dep.of Biochem.Eng.and Sci., Associate Prof., 情報工学部, 助教授 (30125364)
SHUTO Satoshi Hokkaido Univ., Fac.of Farm., Associate Prof., 薬学部, 助教授 (70241346)
|
|---|
| Project Period (FY) |
1996 – 1997
|
| Project Status |
Completed (Fiscal Year 1997)
|
| Budget Amount *help |
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1997: ¥1,900,000 (Direct Cost: ¥1,900,000)
|
|---|
| Keywords | NMDA receptor / neuronal cell death / conformational restriction / cyclopropane / channel blocker / NMDAレセプター / アンタゴニスト / 立体配座固定 / セロトニントランスポーター / 遅発性神経細胞死 / 分子設計 |
|---|
| Research Abstract |
It has been recognized that an efficient NMDA receptor angatonist can be used clinically as a therapeutic agent protecting neuronal cell death. We investigated development of potent NMDA receptor antagonists by a novel conformational restricting method. Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly, because they are fixed in eclipsed conformation to each other. Based on this structural feature of the cyclopropane ring, we devised a new method for restricting the conformation of cyclopropane derivatives. Using this strategy, conformationally restriced analogs of milnacipran, a useful antidepressant, were designed as potent NMDA receptor antagonists, and were synthesized highly enantioselectively from chiral epichlorohydrines. Throughout the synthetic study, we found that nucleophilic addition reactions on cyclopropylcarbaldehyde and-ketones proceeded hihgly stereoselectively via eitherth bisected s-trans or s-cis conformation of the cyclopropylcarbonyl derivatives. The structures of the conformationally restricted analogs detected by the X-ray crystallographic analysis suggested that their conformations can be restricted as we hypothesized.
Some of the synthesized analogs were significantly effective compared with milnacipran as an NMDA receptor antagonists. PPCD,the most strong antagonist developed by us, was identified as a novel class of NMDA receptor channel blockers.
|
