Conformational analysis of the NMDA receptor antagonist (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC) designed by a novel conformational restriction method based on the structural feature of cyclopropane ring.
(1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (2b, PPDC), a new class of potent N-methyl-D-aspartic acid (NMDA) receptor antagonist, was designed based on a new method for restricting the conformation of compounds having a cyclopropane ring. The three-dimensional structures of PPDC obtained by the three different methods of X-ray crystallographic analysis, usual MM2-calculations in vacuum, and MM2 calculations based on the nuclear Overhauser effect (NOE) data in D2O are similar, which are in accord with that hypothesized. These results suggest that this conformational restriction method is particularly effective in designing novel biologically active molecules.
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Sizuka
S
Ono
Kiyoshi
K
Ogawa
Kanako
K
Yamashita
Tamotsu
T
Yamamoto
Yuji
Y
Kazuta
Akira
A
Matsuda
Satoshi
S
Shuto
D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D000078764:Milnacipran; D008958:Models, Molecular; D008968:Molecular Conformation; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C438901:1-phenyl-2-(1-aminopropyl)-N,N-diethylcyclopropanecarboxamide; D003521:Cyclopropanes; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D000078764:Milnacipran