Abstract
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.
Highlights
We have reported the in vitro profile of 1a and 2a, including binding and activation of the μ opioid receptor (μOR), and were first to show that the presence of an N-phenethyl group at position 17 is highly favorable in terms of improved affinity and selectivity at the μOR and potent μOR agonism in vitro13
The results of the present study provide structure-activity relationships (SARs) evidence on the consequences of an N-methyl substitution in morphinan opioids 1–4 by an N-phenethyl in 1a–4a on in vitro and in vivo activities, with molecular docking and molecular dynamics (MD) simulations studies offering a structural basis for the observed pharmacological profiles at the opioid receptors
Pharmacological findings are supported by docking and MD simulations analysis with N-methyl substitute morphine [1] and oxymorphone [2] showing a slightly different orientation in the binding pocket of the μOR compared to their related N-phenethyl analogues, 1a and 2a, respectively
Summary
Undesirable effects (i.e. constipation, respiratory depression, sedation, analgesic tolerance and dependence) of opioids. We have aimed to investigate the effect of the replacement of the N-methyl group in 14-OMO [3] and 14-MM [4] by an N-phenethyl substituent in 3a and 4a, respectively, on in vitro profiles (opioid receptor binding and functional activities), and in vivo behavioural properties (nociception and motor function) in mice. The current work was undertaken to understand the consequences of the substitution of the N-methyl group in N-methylmorphinans 1–4 by an N-phenethyl group in 1a–4a on their pharmacological activities using molecular docking and molecular dynamics (MD) simulations, to gain insights on their binding and subtype profile for opioid receptors. The emerged structure-activity relationships (SARs) in this class of opioid morphinans provide essential information for tuning functional in vitro and in vivo activities towards discovery of effective and safer analgesics for the pain treatment
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