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.
(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.
Kazuta
Yuji
Y
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Japan.
Tsujita
Ryuichi
R
Yamashita
Kanako
K
Uchino
Shigeo
S
Kohsaka
Shinichi
S
Matsuda
Akira
A
Shuto
Satoshi
S
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002540:Cerebral Cortex / Q000737:chemistry; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D006841:Hydrocarbons, Aromatic; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
C438901:1-phenyl-2-(1-aminopropyl)-N,N-diethylcyclopropanecarboxamide; D000928:Antidepressive Agents; D003521:Cyclopropanes; D006841:Hydrocarbons, Aromatic; D016194:Receptors, N-Methyl-D-Aspartate; D012702:Serotonin Antagonists