title: Investigation of Beckett-Casy model 3: synthesis of novel naltrexone derivatives with contracted and expanded D-rings and their pharmacology.
abstract: Novel naltrexone derivatives 7 and 8 with contracted and expanded D-rings were synthesized to investigate the importance of orientation of lone electron pair on the nitrogen for binding abilities to the opioid receptor. Compound 7 showed almost no binding affinity, whereas compound 8 was comparable to naltrexone (6) in binding affinity. Conformational analyses and NOE experiments in D(2)O of compounds 6-8 suggested that the lone electron pairs of compounds 6 and 8 with respective six- and seven-membered D-rings would project in the pseudo-axial orientation, whereas compound 7 with five-membered D-ring would have the lone electron pair directing in pseudo-equatorial position. These results strongly supported the proposal that the axial orientation of the lone electron pair on nitrogen would provide sufficient binding abilities to the opioid receptor and that the 15-16 ethylene moiety in the morphine structure would play a role in fixation of the lone electron pair in the axial direction rather than interaction with the putative cavity in the Beckett-Casy model.
authors.affiliation: School of Pharmacy, Kitasato University, Tokyo, Japan. nagaseh@pharm.kitasato-u.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.forename: Satomi
authors.initials: S
authors.lastname: Imaide
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tomatsu
authors.forename: Shigeto
authors.initials: S
authors.lastname: Hirayama
authors.forename: Toru
authors.initials: T
authors.lastname: Nemoto
authors.forename: Noriko
authors.initials: N
authors.lastname: Sato
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nakajima
authors.forename: Kaoru
authors.initials: K
authors.lastname: Nakao
authors.forename: Hidenori
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Gouda
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
mesh_terms: D004583:Electrons; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry; D011485:Protein Binding; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D011957:Receptors, Opioid; D009271:Naltrexone