title: μ Opioid receptor: novel antagonists and structural modeling.
abstract: The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.
authors.affiliation: Computer-Aided Molecular Design Group, Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Teresa
authors.initials: T
authors.lastname: Kaserer
authors.affiliation: Opioid Research Group, Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Aquilino
authors.initials: A
authors.lastname: Lantero
authors.affiliation: Opioid Research Group, Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidhammer
authors.affiliation: Opioid Research Group, Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Mariana
authors.initials: M
authors.lastname: Spetea
authors.affiliation: Computer-Aided Molecular Design Group, Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D062105:Molecular Docking Simulation; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry; D009292:Narcotic Antagonists / Q000737:chemistry*; D017450:Receptors, Opioid, mu / Q000737:chemistry* / Q000378:metabolism
chemical_list: D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009271:Naltrexone; C024524:beta-funaltrexamine