title: Design, synthesis, and biological evaluation of 14-heteroaromatic-substituted naltrexone derivatives: pharmacological profile switch from mu opioid receptor selectivity to mu/kappa opioid receptor dual selectivity.
abstract: On the basis of a mu opioid receptor (MOR) homology model and the isosterism concept, three generations of 14-heteroaromatically substituted naltrexone derivatives were designed, synthesized, and evaluated as potential MOR-selective ligands. The first-generation ligands appeared to be MOR-selective, whereas the second and the third generation ones showed MOR/kappa opioid receptor (KOR) dual selectivity. Docking of ligands 2 (MOR selective) and 10 (MOR/KOR dual selective) to the three opioid receptor crystal structures revealed a nonconserved-residue-facilitated hydrogen-bonding network that could be responsible for their distinctive selectivity profiles. The MOR/KOR dual-selective ligand 10 showed no agonism and acted as a potent antagonist in the tail-flick assay. It also produced less severe opioid withdrawal symptoms than naloxone in morphine-dependent mice. In conclusion, ligand 10 may serve as a novel lead compound to develop MOR/KOR dual-selective ligands, which might possess unique therapeutic value for opioid addiction treatment.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University , 800 East Leigh Street, Richmond, Virginia 23298, United States.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Yuan
authors.forename: Saheem A
authors.initials: SA
authors.lastname: Zaidi
authors.forename: Orgil
authors.initials: O
authors.lastname: Elbegdorj
authors.forename: Lindsey C K
authors.initials: LC
authors.lastname: Aschenbach
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.forename: David L
authors.initials: DL
authors.lastname: Stevens
authors.forename: Krista L
authors.initials: KL
authors.lastname: Scoggins
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016466:CHO Cells; D060326:Chemistry Techniques, Synthetic; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009271:Naltrexone / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation; D017473:Receptors, Opioid, kappa / Q000737:chemistry / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009271:Naltrexone