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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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Nieto CT,Gonzalez-Nunez V,Rodríguez RE,Diez D,Garrido NM

doi

10.1016/j.ejmech.2015.06.025

subject

Has Abstract

pub_date

2015-08-28 00:00:00

pages

150-62

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(15)30100-8

journal_volume

101

pub_type

杂志文章

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