Abstract
Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led to N-methylmorphinan-6-ones differently substituted at positions 5 and 14 as μ-OR agonists inducing potent analgesia and fewer undesirable effects. Herein we present the first thorough molecular modeling study and structure–activity relationship (SAR) explorations aided by docking and molecular dynamics (MD) simulations of 14-oxygenated N-methylmorphinan-6-ones to gain insights into their mode of binding to the μ-OR and interaction mechanisms. The structure of activated μ-OR provides an essential model for how ligand/μ-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these μ-agonists share and distinguish them. The molecular docking outcomes indicate the crucial role of the relative orientation of the ligand in the μ-OR binding site, influencing the propensity of critical non-covalent interactions that are required to facilitate ligand/μ-OR interactions and receptor activation. The MD simulations point out minor differences in the tendency to form hydrogen bonds by the 4,5α-epoxy group, along with the tendency to affect the 3–7 lock switch. The emerged SARs reveal the subtle interplay between the substituents at positions 5 and 14 in the morphinan scaffold by enabling the identification of key structural elements that determine the distinct pharmacological profiles. This study provides a significant structural basis for understanding ligand binding and μ-OR activation by the 14-oxygenated N-methylmorphinan-6-ones, which should be useful for guiding drug design.
Highlights
Opioids, such as morphine (Figure 1), have a long history of clinical use as the most effective analgesic drugs for the alleviation of moderate to severe acute and chronic pain.[1]
Encouraged by the interesting outcomes on the in vitro and in vivo pharmacology of N-methylmorphinan-6-ones differently substituted at positions 5 and 14 designed by our group,[8,9] we report for the first time on an explorative structure−activity relationship (SAR) study aiming to gain mechanistic insights via molecular docking and molecular dynamics (MD) simulations of ligand/μ-opioid receptor (μ-OR) interactions of these potent μ-OR agonists
We have presented the first thorough molecular modeling study aided by docking and MD simulations of μ-OR agonists 1−6
Summary
Opioids, such as morphine (Figure 1), have a long history of clinical use as the most effective analgesic drugs for the alleviation of moderate to severe acute and chronic pain.[1]. Has been the basis of numerous drug developments, and several molecules with distinctive pharmacology are available for patient use or employed as molecular probes in vitro and in vivo.[2−4] The morphinan class of opioid analgesics includes naturally occurring alkaloids (e.g., morphine, codeine), semisynthetic derivatives (e.g., oxycodone, oxymorphone, buprenorphine), and synthetic analogues (e.g., levorphanol, butorphanol). They exert the analgesic action primarily via activation of the μ-opioid receptor (μ-OR).[1,4] the desired analgesic effect is accompanied by undesirable side effects (e.g., respiratory depression, sedation, nausea, or constipation), and a considerable proneness to the development of tolerance and dependence is well-known, albeit most often associated with their long-term use.[1,4,5] The μ-OR, as a member of the Family A (rhodopsin-like) G protein-coupled receptors (GPCRs) with a common seven transmembrane (7TM) helical architecture,[6,7] has received constantly significant attention as a prominent drug discovery target toward pain treatment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
