Design, synthesis, pharmacological evaluation and molecular dynamics of β-amino acids morphan-derivatives as novel ligands for opioid receptors

• Published in: European journal of medicinal chemistry Vol. 101; pp. 150 - 162
• Main Authors: Nieto, Carlos T., Gonzalez-Nunez, Veronica, Rodríguez, Raquel E., Diez, David, Garrido, Narciso M.
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 28.08.2015; Elsevier
• Subjects: Amino Acids - chemistry; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Design; Humans; Life Sciences & Biomedicine; Ligands; Molecular dynamics; Molecular Dynamics Simulation; Molecular Structure; Morphans; Morphinans - chemical synthesis; Morphinans - chemistry; Morphinans - metabolism; Pharmacology & Pharmacy; Radioligand binding; Receptors, Opioid, mu - chemistry; Receptors, Opioid, mu - metabolism; Science & Technology; Structure-Activity Relationship; β-amino acids; μ opioid receptor; Molecular dynamics; μ opioid receptor; β-amino acids; Radioligand binding; Morphans; ASYMMETRIC-SYNTHESIS; ANTAGONIST; mu opioid receptor; MODEL; beta-amino acids; DENSITY; BIOLOGICAL EVALUATION; FORCE-FIELD; CONSTRAINTS; SIMULATIONS; PROTEINS; BINDING
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.06.025

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. [Display omitted] •A structure-based drug design study was developed to design new opioid ligands.•Best docking candidates were synthesized employing orthogonal synthetic methods.•Four top compounds were selected due to their affinity for the mu opioid receptor.•MD simulations described their binding topology, which are different from morphine.•MM/PBSA ranking matched the order of binding affinity seen in the biological test.