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6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

preprint
submitted on 12.03.2021, 03:23 and posted on 16.03.2021, 10:54 by Nicholas S. Akins, Nisha Mishra, Hannah M. Harris, Narendar Dudhipala, Seong Jong Kim, Adam W. Keasling, Soumyajit Majumdar, Jordan K. Zjawiony, Nicole Ashpole, Hoang V. Le
Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. In vivo studies on the lead dual kappa and mu opioid receptor agonist, compound 10, showed that it produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

Funding

COBRE Phase III Transitional Center

National Institute of General Medical Sciences

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History

Email Address of Submitting Author

hle@olemiss.edu

Institution

University of Mississippi

Country

United States

ORCID For Submitting Author

0000-0002-8392-7113

Declaration of Conflict of Interest

The authors report no conflict of interest.

Version Notes

Communication version

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