6,5-fused ring, C2-salvinorin ester, dual kappa and mu opioid receptor agonists as analgesics devoid of anxiogenic effects.

Authors: AKINS, NICHOLAS - University Of Mississippi; MISHRA, NISHA - University Of Mississippi; HARRIS, HANNAH - University Of Mississippi; DUDHIPALA, NARENDAR - University Of Mississippi; Kim, Seong; KEASLING, ADAM - University Of Mississippi; ZJAWIONY, JORDAN - University Of Mississippi; ASHPOLE, NICOLE - University Of Mississippi; LE, HOANG - University Of Mississippi

Submitted to: ChemMedChem
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/18/2022
Publication Date: 1/18/2022
Citation: Akins, N.S., Mishra, N., Harris, H.M., Dudhipala, N., Kim, S., Keasling, A.W., Zjawiony, J.K., Ashpole, N.M., Le, H.V. 2022. 6,5-fused ring, C2-salvinorin ester, dual kappa and mu opioid receptor agonists as analgesics devoid of anxiogenic effects.. ChemMedChem. https://doi.org/10.1002/cmdc.202100684.
DOI: https://doi.org/10.1002/cmdc.202100684

Interpretive Summary: Selective agonists of classical opioid receptors, including kappa, mu, and delta-opioid receptors, are commonly used and clinically efficacious against a number of anxiety, depression, and chronic pain state. However, these compounds often result in many serious and harmful adverse effects, such as addiction, dysphoria, reduced bowel motility, tolerance, convulsions, and overdose. Recently, compounds exhibiting dual agonism to the opioid receptors have been suggested to temper undesirable adverse effects while retaining analgesic activity. The present study introduced various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. The compounds were subjected to in vitro evaluation to determine their affinity, efficacy, and functionality on classical opioid receptors. The results showed that some of these compounds have dual agonism on KOR and MOR, while some have triple agonism on KOR, MOR, and DOR that were selected for in vivo studies. The 7-fluoro-1H-indole derivative exerted significant anti-nociceptive effects in the hot plate test but not in the tail-flick test, suggesting the anti-nociceptive effect of it was mediated. Also, the derivative did not cause anxiogenic or anxiolytic effects in the elevated plus-maze, thus providing further strong evidence that dual KOR and MOR agonists have therapeutic advantages over selective opioid receptor agonists.

Technical Abstract: Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects such as addiction, dysphoria, reduced bowel motility, tolerance, convulsions, and overdose. 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. Salvinorin A is the main active ingredient in the hallucinogenic plant Salvia divinorum. It is one of the most potent, naturally occurring opioid agonists with high selectivity and affinity for ' opioid receptor. It has the potential to be beneficial in therapy of various central nervous system (CNS) disorders. Due to its strong hallucinating effects, salvinorin A has never advanced to clinical trials, but has been used as an important prototype for the development of related drug candidates. 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 opioid receptors. 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.