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
S. Shuto et al., 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, Journal of medicinal chemistry, 41(18), 1998, pp. 3507-3514
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.