title: A new consistent model explaining structure (conformation)-activity relationships of opiates with mu-selectivity.
abstract: Several different classes of opiates such as PET (7-alpha-(1-Hydroxy-1-methyl-3-phenylpropyl)-6,14-endo-ethenotetra - hydronorthebaine), phenazocine, fentanyl, carfentanil, ohmefentanyl, prodine derivatives, methadone and etonitazene have been investigated using the molecular modelling program package SYBYL and the TRIPOS empirical force field. Comparison of the energetically optimized structures and their corresponding molecular electrostatic potentials was used for the development of a new model of conformation-activity relationships of mu-selective opiates. We considered six important spatial positions of these molecules which were assumed to be directly implicated in the interaction with the opiate receptor. We found that these opiates may bind to the receptor with their protonated nitrogen atom assuming one or the other of two different orientations. The obtained results offer new insights into important receptor interactions and the diverse opiate activities of all the compounds examined can be explained in a unified manner. For example, the most active ohmefentanyl stereo-isomer was predicted on the basis of the proposed model.
authors.affiliation: Department of Biochemistry/Biotechnology, Martin-Luther-University, Halle, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Brandt
authors.forename: A
authors.initials: A
authors.lastname: Barth
authors.forename: H D
authors.initials: HD
authors.lastname: Höltje
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D005283:Fentanyl / Q000031:analogs & derivatives / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D009294:Narcotics / Q000737:chemistry / Q000494:pharmacology*; D010620:Phenazocine / Q000737:chemistry / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014055:Tomography, Emission-Computed
chemical_list: D000700:Analgesics; D009294:Narcotics; D017450:Receptors, Opioid, mu; C037016:F 7302; D010620:Phenazocine; D005283:Fentanyl