Synthesis of derivatives of (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC) modified at the 1-aromatic moiety as novel NMDA receptor antagonists: the aromatic group is essential for the activity |
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Authors: | Kazuta Yuji Tsujita Ryuichi Yamashita Kanako Uchino Shigeo Kohsaka Shinichi Matsuda Akira Shuto Satoshi |
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Institution: | a Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan b Institute for Life Science Research, Asahi Chemical Co., Ltd., Ohito-cho, Shizuoka 410-2321, Japan c Department of Neurochemistry, National Institute of Neuroscience, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan |
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Abstract: | (1S,2R)-1-Phenyl-2-(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC, 4a), which is a conformationally restricted analogue of antidepressant milnacipran (±)-1], is a new class of potent noncompetitive NMDA receptor antagonists. A series of PPDC analogues modified at the 1-phenyl moiety, that is, the analogue 6 lacking 1-phenyl group, the 1-(fluorophenyl) analogues 4b,c,d, the 1-(methylphenyl) analogues 4e–g and the 1-(naphthyl) analogues 4h,i were synthesized. Analogue 6, lacking the 1-phenyl group, was completely inactive showing that the aromatic moiety is essential for the NMDA receptor binding. Among the analogues synthesized, the 1-o-fluorophenyl and 1-m-fluorophenyl analogues 4b and 4c showed potent affinities for the NMDA receptor IC50=0.16±0.001 μM (4b), 0.15±0.02 μM (4c)], which were improved to some extent compared to those of the parent compound PPDC (IC50=0.20±0.02 μM). On the other hand, compounds 4b and 4c showed none of the 5-HT-uptake inhibitory effect, while PPDC turned out to be a weak 5-HT-uptake inhibitor. |
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