title: Design, synthesis, pharmacological evaluation and molecular dynamics of β-amino acids morphan-derivatives as novel ligands for opioid receptors.
abstract: Structure-Activity Relationship (SAR) is a current approach in the design of new pharmacological agents. We previously reported the synthesis of a novel analogue of morphine, a 2-azabicyclo[3.3.1]nonane, which contains a β-amino acid. This bicyclic core exhibits two distinctive chemical handles for further elaboration, which allowed us to create a library of morphan-containing compounds by in silico molecular docking on the μ opioid receptor. Lead candidates were synthesized and biological tests were performed to evaluate their ability to bind to opioid receptors. The four top compounds, three phenyl esters and an N-phenylethyl morphan derivative, were selected for Molecular Dynamics simulations to get topological and thermodynamic information. Aromatic morphan derivatives displayed an interacting domain which fits into a hydrophobic cleft and the effect of the substituents in their affinity was explained by the differences in the calculated binding free energies. Our results indicate that the 3D arrangement of the aromatic ring in the morphine derivatives is not a key issue for a specific ligand - μ receptor interaction. Thus, these morphan derivatives represent a new class of opioid receptor ligands which may be of great use in the clinical practice.
authors.affiliation: Departamento de Química Orgánica, Faculty of Chemistry, Universidad de Salamanca, Spain.
authors.forename: Carlos T
authors.initials: CT
authors.lastname: Nieto
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Neuroscience Institute of Castilla y Leon (INCyL), University of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), Spain.
authors.forename: Veronica
authors.initials: V
authors.lastname: Gonzalez-Nunez
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Neuroscience Institute of Castilla y Leon (INCyL), University of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), Spain.
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Rodríguez
authors.affiliation: Departamento de Química Orgánica, Faculty of Chemistry, Universidad de Salamanca, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Diez
authors.affiliation: Departamento de Química Orgánica, Faculty of Chemistry, Universidad de Salamanca, Spain. Electronic address: nmg@usal.es.
authors.forename: Narciso M
authors.initials: NM
authors.lastname: Garrido
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D008024:Ligands; D009019:Morphinans; D017450:Receptors, Opioid, mu
keywords: Molecular dynamics; Morphans; Radioligand binding; β-amino acids; μ opioid receptor