title: Molecular modeling and 3D-QSAR studies of indolomorphinan derivatives as kappa opioid antagonists.
abstract: Molecular modeling and 3D-QSAR studies were performed on 31 indolomorphinan derivatives to evaluate their antagonistic behaviors on kappa opioid receptor and provide information for further modification of this kind of compounds. Best predictions were obtained with CoMFA standard model (q2 = 0.693, N = 4, r2 = 0.900) and CoMSIA combined model (q2 = 0.617, N = 4, r2 = 0.904). Both models were further validated by an external test set of eight compounds with satisfactory predictions: r2 = 0.607 for CoMFA and r2 = 0.701 for CoMSIA. In addition, the 3D structure of human kappa opioid receptor was constructed based on the crystal structure of bovine rhodopsin, and the CoMSIA contour plots were then mapped into the structural model of kappa opioid receptor-GNTI complex to identify key residues, which might account for kappa antagonist potency and selectivity. The roles of nonconserved Glu297 and conserved Lys227 of human kappa opioid receptor were then discussed.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 200032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.forename: You-Li
authors.initials: YL
authors.lastname: Zheng
authors.forename: Zhui-Bai
authors.initials: ZB
authors.lastname: Qiu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D017124:Conserved Sequence; D019791:Guanidine / Q000737:chemistry; D006146:Guanidines; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009019:Morphinans / Q000737:chemistry* / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D012243:Rhodopsin / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: C411465:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan; D006146:Guanidines; D007211:Indoles; D009019:Morphinans; D017473:Receptors, Opioid, kappa; D009271:Naltrexone; D012243:Rhodopsin; D019791:Guanidine