A study on development of inhibitors for neuronal cell death

现已认识到，一种有效的NMDA受体激动剂可用于临床作为保护神经细胞死亡的治疗剂。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。环丙烷环上的相邻取代基相互之间产生相当大的空间斥力，因为它们彼此以遮蔽的构象固定。基于环丙烷环的这种结构特征，我们设计了一种新的方法来限制环丙烷衍生物的构象。利用这一策略，构象受限的米那普兰类似物被设计为有效的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，我们发现环丙基甲醛和-酮的亲核加成反应是通过环丙基甲酰衍生物的S-反式或S-顺式二分构象进行的。通过X-射线晶体分析检测到的构象受限类似物的结构表明，它们的构象是可以限制的，其中一些合成的类似物与作为NMDA受体拮抗剂的米那普兰相比具有显著的效果。PPCD是我们开发的最强的拮抗剂，被鉴定为一类新型的NMDA受体通道阻滞剂。

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.