A study on development of inhibitors for neuronal cell death

神经细胞死亡抑制剂的开发研究

• 批准号: 08557134
• 负责人: MATSUDA Akira
• 金额: $ 1.22万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08557134/
• 关键词: 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

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.

一种高效的NMDA受体止痛剂可以作为一种保护神经细胞死亡的治疗药物用于临床。我们通过一种新的构象限制方法研究了有效的NMDA受体拮抗剂的开发。在环丙烷环上相邻的取代基相互之间产生非常明显的空间排斥，因为它们以重叠构象相互固定。基于环丙烷环的这一结构特征，我们设计了一种限制环丙烷衍生物构象的新方法。利用这一策略，将milnacpran（一种有用的抗抑郁药）的构象限制类似物设计为有效的NMDA受体拮抗剂，并以手性环氧氯丙烷为原料高度对映选择性地合成。在整个合成研究中，我们发现环丙基羰基衍生物的亲核加成反应通过两等分的s-反式或s-顺式构象进行高度立体选择性。x射线晶体学分析检测到的构象限制类似物的结构表明，它们的构象可以像我们假设的那样受到限制。一些合成的类似物作为NMDA受体拮抗剂与milnacpran相比效果显著。PPCD是一种新型的NMDA受体通道阻滞剂，是我们开发的最强大的拮抗剂。

项目成果

S.Shuto etal.,: "Conformational restriction by repulsion between adjacent substituents on a cyclopropane ring" J.Org.Chem.61. 915-923 (1996)

S.Shuto 等人：“环丙烷环上相邻取代基之间的排斥力造成的构象限制”J.Org.Chem.61。

S.Shuto et al.: "Synthesis and biological activity of conformationally restricted analogs of milnacipran : (1S,1R)-1-Phenyl-2- [(S)-1-aminopropyl] -N,N-diethylcyclopropanecarboxamide, an efficient noncompetitiveN-methyl-D-aspartic acid receptor antagonist

S.Shuto 等人：“米那普仑构象限制类似物的合成和生物活性：(1S,1R)-1-苯基-2-[(S)-1-氨基丙基]-N,N-二乙基环丙烷甲酰胺，一种有效的非竞争性N

S.Shuto et al.: "(±) - (z)-2-Aminomethyl-1-phenylcyclopropanecarboxamide derivatives as a new prototype of NMDA receptor antagonists." J.Med.Chem.38. 2964-2968 (1995)

S.Shuto 等人：“(±) - (z)-2-氨基甲基-1-苯基环丙烷甲酰胺衍生物作为 NMDA 受体拮抗剂的新原型。”J.Med.Chem.38 2964-2968 (1995)。

S.Ono etal.,: "Highly stereoselective nucleophilic addition to cyclopropyl carbonyls" Tetrahedron Lett.37. 221-224 (1996)

S.Ono 等人：“环丙基羰基的高度立体选择性亲核加成”Tetrahedron Lett.37。

S.Shuto et al.: "Conformational restriction by repulsion between adjacent substituents on a cyclopropane ring : Design and enantioselective synthesis of 1-phenyl-2- (1-aminoalkyl) cyclopropane-N,N-diethylcarboxamides as potent NMDA receptor antagonists."

S.Shuto 等人：“通过环丙烷环上相邻取代基之间的排斥来限制构象：设计和对映选择性合成 1-苯基-2-(1-氨基烷基)环丙烷-N,N-二乙基甲酰胺作为有效的 NMDA 受体拮抗剂。”