(+/-)-(Z)-2-(aminomethyl)-1-phenylcyclopropanecarboxamide derivatives as a new prototype of NMDA receptor antagonists.
(+/-)-(Z)-2-(Aminomethyl)-1-phenylcyclopropane-N,N-diethylcarbo xamide (milnacipran, 1), a clinically useful antidepressant, and its derivatives were prepared by 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 microM; 7, 13 +/- 2.1 microM; 8, 88 +/- 1.4 microM; 12, 10 +/- 1.2 microM). These also protected mice from NMDA-induced lethality. These compounds would be important as anovel prototype for designing potent NMDA-receptor antagonists because of their characteristic structure, which clearly differentiated them from known competitive and noncompetitive antagonists to the receptor.
Shuto
S
S
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Takada
H
H
Mochizuki
D
D
Tsujita
R
R
Hase
Y
Y
Ono
S
S
Shibuya
N
N
Matsuda
A
A
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D000078764:Milnacipran; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium
D000928:Antidepressive Agents; D003521:Cyclopropanes; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D016291:Dizocilpine Maleate; D000078764:Milnacipran