Kazuta Yuji, Tsujita Ryuichi, Yamashita Kanako, Uchino Shigeo, Kohsaka Shinichi, Matsuda Akira, Shuto Satoshi
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Japan.
Bioorg Med Chem. 2002 Dec;10(12):3829-48. doi: 10.1016/s0968-0896(02)00346-2.
(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 [IC(50)=0.16+/-0.001 microM (4b), 0.15+/-0.02 microM (4c)], which were improved to some extent compared to those of the parent compound PPDC (IC(50)=0.20+/-0.02 microM). 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.
(1S,2R)-1-苯基-2-[(S)-1-氨基丙基]-N,N-二乙基环丙烷甲酰胺（PPDC，4a）是抗抑郁药米那普明[(+/-)-1]的构象受限类似物，是一类新型强效非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂。合成了一系列在1-苯基部分进行修饰的PPDC类似物，即缺少1-苯基的类似物6、1-(氟苯基)类似物4b、c、d、1-(甲基苯基)类似物4e - g和1-(萘基)类似物4h、i。缺少1-苯基的类似物6完全无活性，表明芳香部分对NMDA受体结合至关重要。在合成的类似物中，1-邻氟苯基和1-间氟苯基类似物4b和4c对NMDA受体显示出强效亲和力[半数抑制浓度（IC(50)）=0.16±0.001微摩尔（4b），0.15±0.02微摩尔（4c）]，与母体化合物PPDC（IC(50)=0.20±0.02微摩尔）相比有一定程度的提高。另一方面，化合物4b和4c没有显示出5-羟色胺（5-HT）摄取抑制作用，而PPDC被证明是一种弱5-HT摄取抑制剂。
