title: Synthesis of (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC) derivatives modified at the carbamoyl moiety as a new class of NMDA receptor antagonists.
abstract: (1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC, ), which is a conformationally restricted analogue of the antidepressant milnacipran [(+/-)-1], represents a new class of potent NMDA receptor antagonists. A series of PPDC analogues modified at the carbamoyl moiety were synthesized. Among these, (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-dipropylcyclopropanecarboxamide (4d) was identified as the most potent NMDA receptor antagonist in this series and clearly reduced the MMDA receptor mediated potentiation of rat hippocampal slices, a model of long-term potentiation (LTP). The three-dimensional structure of 4d was also analyzed in detail to clarify the receptor-binding conformation.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kazuta
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tsujita
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ogawa
authors.forename: Tadami
authors.initials: T
authors.lastname: Hokonohara
authors.forename: Kanako
authors.initials: K
authors.lastname: Yamashita
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Morino
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D017774:Long-Term Potentiation; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C438901:1-phenyl-2-(1-aminopropyl)-N,N-diethylcyclopropanecarboxamide; D003521:Cyclopropanes; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin