Synthesis of derivatives of (1 S,2 R)-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

• Published in: Bioorganic & medicinal chemistry 2002-12, Vol.10 (12), p.3829-3848
• Main Authors: Kazuta, Yuji, Tsujita, Ryuichi, Yamashita, Kanako, Uchino, Shigeo, Kohsaka, Shinichi, Matsuda, Akira, Shuto, Satoshi
• Format: Article
• Language: English
• Subjects: Animals; Antidepressive Agents - chemical synthesis; Antidepressive Agents - pharmacology; Biological and medical sciences; Cerebral Cortex - chemistry; Cyclopropanes - chemical synthesis; Cyclopropanes - pharmacology; Glutamatergic system (aspartate and other excitatory aminoacids); Hydrocarbons, Aromatic; Inhibitory Concentration 50; Medical sciences; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Radioligand Assay; Rats; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - pharmacology; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(02)00346-2

(1 S,2 R)-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 μM ( 4b), 0.15±0.02 μM ( 4c)], which were improved to some extent compared to those of the parent compound PPDC (IC 50=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. Graphic