Discovery and structure-activity relationships of 4-aminoquinazoline derivatives, a novel class of opioid receptor like-1 (ORL1) antagonists.
Synthesis and structure-activity relationship studies of a series of 4-aminoquinazoline derivatives led to the identification of (1R,2S)-17, N-[(1R,2S)-2-({2-[(4-chlorophenyl)carbonyl]amino-6-methylquinazolin-4-yl}amino)cyclohexyl]guanidine dihydrochloride, as a highly potent ORL1 antagonist with up to 3000-fold selectivity over the mu, delta, and kappa opioid receptors. Molecular modeling clarified the structural factors contributing to the high affinity and selectivity of (1R,2S)-17.
Okano
Masahiko
M
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 14 Nishinosho-Monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan. m.okano@po.nippon-shinyaku.co.jp
Mito
Jun
J
Maruyama
Yasufumi
Y
Masuda
Hirofumi
H
Niwa
Tomoko
T
Nakagawa
Shin-Ichiro
S
Nakamura
Yoshitaka
Y
Matsuura
Akira
A
D055808:Drug Discovery; D008958:Models, Molecular; D009292:Narcotic Antagonists; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D011957:Receptors, Opioid; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
D009292:Narcotic Antagonists; D011799:Quinazolines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor