title: A pseudoreceptor docking study of 4,5-alpha-epoxymorphinans with a range of dielectric constants.
abstract: Thirteen 4,5-epoxymorphinan mu agonists with established analgesic action were docked into an Asp-Lys-His-Phe pseudoreceptor complex under a range of distance-dependent dielectric conditions. The number of compounds with potential energies of the docked complexes that agreed in rank order with corresponding analgesic potencies was determined for each condition. Two dielectric conditions, n-decane (1.991) and ethanol (24.3), enabled the greatest number of compounds to relate to their pseudoreceptors with each having 9 and 8 successes respectively. Both of these conditions demonstrated unique influences on the types of structures that were successfully docked. For example, the morphine stereoisomer alpha-isomorphine, the geometric isomer B/C trans-morphine, and the 8-position-substituted gamma-isomorphine were successes in the n-decane condition, whereas the ethanol condition produced the substituted codeine derivatives dihydrocodeinone and dihydroxycodeinone. These findings emphasize the importance of dielectric influence when developing force-field modeled quantitative structure-activity relationships for a closely related homologous series.
authors.affiliation: Advanced Scientific Computing Laboratory, National Cancer Institute-FCRDC, PRI/DynCorp, Frederick, MD 21702.
authors.forename: R
authors.initials: R
authors.lastname: Gussio
authors.forename: S
authors.initials: S
authors.lastname: Pou
authors.forename: J H
authors.initials: JH
authors.lastname: Chen
authors.forename: G W
authors.initials: GW
authors.lastname: Smythers
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D004563:Electrochemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009019:Morphinans / Q000737:chemistry* / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry; D011957:Receptors, Opioid / Q000737:chemistry* / Q000187:drug effects; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D009019:Morphinans; D009842:Oligopeptides; D011957:Receptors, Opioid