Date of Award
Ph.D. in Pharmaceutical Sciences
Pharmaceutics and Drug Delivery
Hoang V. Le
David A. Colby
Opioid receptors (OR) are expressed throughout both the peripheral and central nervous system and play crucial roles in the modulation of antinociception, addiction, anxiety, and depression. Salvinorin A, the main isolate of the hallucinogenic plant Salvia divinorum, is one of the most potent naturally occurring kappa opioid receptor agonists. Salvinorin A possesses beneficial effects as a therapeutic in a variety of CNS disorders, but due to its strong hallucinating, anxiogenic effects, and short half-life(t1/2), it has never advanced to clinical trials. Instead, salvinorin A has been used as an important prototype for the development of related drug candidates. Our initial systematic study of C2-ester linked-heterocyclic salvinorin-based analogs indicated that simple modifications of the substituents can result in large changes in OR activity. This study also identified a variety of selective and non-selective opioid receptor agonists. Additionally, our lab has completed the synthesis, computational, and biological evaluation of the C2 amide and triazole linked analogs of salvinorin. This data elucidated the role the linker, at the C2 position, possessed in opioid receptor activity, selectivity, and cellular signaling. (G-protein vs. ?-arrestin). Alternatively, exciting preliminary results suggested salvinorin-based KOR antagonists can potentially attenuate spontaneous motor behaviors indicative of psychostimulant withdrawal. Our lab has also completed extensive docking protocols of salvinorin-based antagonists to determine residues that are vital for function, selectivity, and potency to the classical OR’s. Future work entails advancement of lead compounds to in vivo models for pain, depression, anxiety, and drug abuse symptomology. Overall, the work entailed in this dissertation will provide molecular insights into the development of salvinorin-based compounds for desired activity, functionality, and cellular signaling to the classical opioid receptors.
Akins, Nicholas S., "DESIGN AND SYNTHESIS OF SALVINORIN-BASED COMPOUNDS FOR THE OPIOID RECEPTORS." (2021). Electronic Theses and Dissertations. 1981.
Emphasis: Medicinal Chemistry