(+ Z)-2-(AMINOMETHYL)-1-PHENYLCYCLOPROPANECARBOXAMIDE DERIVATIVES AS A NEW PROTOTYPE OF NMDA RECEPTOR ANTAGONISTS/

ethyl)-1-phenylcyclopropane-N,N-diethylcarboxamide (milnacipran, 1), a clinically useful antidepressant, and its derivatives were prepared b y an improved method and were evaluated as NMDA receptor antagonists. Of these, milnacipran (1), its N-methyl and N,N-dimethyl derivatives, 7 and 8, respectively, and its homologue 12 at the aminomethyl moiety had binding affinity for the receptor in vitro (IC50: 1, 6.3 +/- 0.3 m u M; 7, 13 +/- 2.1 mu M; 8, 88 +/- 1.4 mu M; 12, 10 +/- 1.2 mu M). The se also protected mice from NMDA-induced lethality. These compounds wo uld be important as anovel prototype for designing potent NMDA-recepto r antagonists because of their characteristic structure, which clearly differentiated them from known competitive and noncompetitive antagon ists to the receptor.