title: Discovery and structure-activity relationships of 4-aminoquinazoline derivatives, a novel class of opioid receptor like-1 (ORL1) antagonists.
abstract: 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.
authors.affiliation: 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
authors.forename: Masahiko
authors.initials: M
authors.lastname: Okano
authors.forename: Jun
authors.initials: J
authors.lastname: Mito
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Maruyama
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Masuda
authors.forename: Tomoko
authors.initials: T
authors.lastname: Niwa
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuura
mesh_terms: 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
chemical_list: D009292:Narcotic Antagonists; D011799:Quinazolines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor