N-Phenethyl Substitution in 14-Methoxy-N-methylmorphinan-6-ones Turns Selective µ Opioid Receptor Ligands into Dual µ/δ Opioid Receptor Agonists

Autor:	Dumitrascuta, Maria, Bermudez, Marcel, Ben Haddou, Tanila, Guerrieri, Elena, Schläfer, Lea, Ritsch, Andreas, Hosztafi, Sandor, Lantero, Aquilino, Kreutz, Christoph, Massotte, Dominique, Schmidhammer, Helmut, Wolber, Gerhard, Spetea, Mariana
Přispěvatelé:	Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	Male Receptors Opioid mu lcsh:Medicine Medicinal chemistry Drug development CHO Cells Ligands Article Cell Line Mice Structure-Activity Relationship Cricetulus G protein-coupled receptors Receptors Opioid delta Animals Humans lcsh:Science Pharmacology Morphine Drug discovery Cheminformatics lcsh:R Analgesics Opioid Morphinans Preclinical research [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] lcsh:Q Molecular modelling
Zdroj:	Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) Scientific Reports Scientific Reports, Nature Publishing Group, 2020, 10 (1), ⟨10.1038/s41598-020-62530-w⟩
ISSN:	2045-2322
DOI:	10.1038/s41598-020-62530-w
Popis:	Morphine and structurally-derived compounds are µ opioid receptor (µOR) agonists, and the most effective analgesic drugs. However, their usefulness is limited by serious side effects, including dependence and abuse potential. The N-substituent in morphinans plays an important role in opioid activities in vitro and in vivo. This study presents the synthesis and pharmacological evaluation of new N-phenethyl substituted 14-O-methylmorphinan-6-ones. Whereas substitution of the N-methyl substituent in morphine (1) and oxymorphone (2) by an N-phenethyl group enhances binding affinity, selectivity and agonist potency at the µOR of 1a and 2a, the N-phenethyl substitution in 14-methoxy-N-methylmorphinan-6-ones (3 and 4) converts selective µOR ligands into dual µ/δOR agonists (3a and 4a). Contrary to N-methylmorphinans 1–4, the N-phenethyl substituted morphinans 1a–4a produce effective and potent antinociception without motor impairment in mice. Using docking and molecular dynamics simulations with the µOR, we establish that N-methylmorphinans 1–4 and their N-phenethyl counterparts 1a–4a share several essential receptor-ligand interactions, but also interaction pattern differences related to specific structural features, thus providing a structural basis for their pharmacological profiles. The emerged structure-activity relationships in this class of morphinans provide important information for tuning in vitro and in vivo opioid activities towards discovery of effective and safer analgesics.
Databáze:	OpenAIRE
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