SYNTHESIS AND BIOLOGICAL-ACTIVITY OF CONFORMATIONALLY RESTRICTED ANALOGS OF MILNACIPRAN - INO-2-PROPYNYL]-N,N-DIETHYLCYCLOPROPANECARBOXAMIDE IS A NOVEL CLASS OF NMDA RECEPTOR-CHANNEL BLOCKER

Conformationally restricted analogues of (+/-)-(Z)-2-aminomethyl-1-phe nyl-N, N-diethylcyclopropanecarboxamide [milnacipran, (+/-)-1] were de signed on the basis of its characteristic cyclopropane structure and w ere synthesized enantioselectively to develop efficient NMDA receptor antagonists. Among these analogues, (1S,2R)-1-phenyl-2-[(R)-1-amino-2- propynyl]- N,N-diethylcyclopropanecarboxamide (2d) had one of the most potent affinities for the receptor, with a K-i value of 0.29 mu M. Th e blockade of NMDA receptor channels expressed by Xenopus oocytes by 2 d was investigated in detail, and 2d was identified as a new class of open channel blocker against this receptor.