A study on development of inhibitors for neuronal cell death

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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.