Selective agonists of classical opioid receptors, including kappa (κ, KOR), mu (μ, MOR), and delta opioid receptor (δ, DOR), are commonly used and clinically efficacious against a number of anxiety, depression, and chronic pain states. Unfortunately, these compounds often result in many serious and harmful adverse effects, such as addiction, dysphoria, reduced bowel motility, tolerance, convulsions, and overdose. Our lab has introduced 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 KOR and MOR, while some have triple agonism on KOR, MOR, and DOR. In vivo studies on our lead dual KOR and MOR agonist showed that it produced analgesic activity while avoiding anxiogenic effects in murine models. We also synthesized and studied various amide and triazole likers at C2 of the salvinorin scaffold and elucidated their roles in the opioid receptor activity, selectivity, and cellular signaling, and discovered the most potent salvinorin-based selective MOR agonist. In addition, we studied a salvinorin-based KOR antagonist as well as norbinaltorphimine (nor-BNI) on C57BL/6N mice for acute cocaine withdrawal, and carried out computational studies, including induced-fit docking, mutagenesis, and molecular dynamics simulation, to identify pertinent interactions between the salvinorin-based antagonist and KOR. Our results support the notion that KOR antagonism via selective, short-acting antagonists may reduce the negative affective symptoms associated with psychostimulant withdrawal, potentially reducing relapse and improving recovery outcomes. Overall, our work has provided molecular insights into the development of salvinorin-based compounds for desired activity, functionality, and cellular signaling to the classical opioid receptors.

Synthesis, computational studies and behavioral evaluation of novel salvinorin-based opioid receptor agonists and antagonists

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.