Electronic Theses and Dissertations

Date of Award

1-1-2021

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

Department

Pharmaceutics and Drug Delivery

First Advisor

Hoang V. Le

Second Advisor

David A. Colby

Third Advisor

Sudeshna Roy

Relational Format

dissertation/thesis

Abstract

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.

Concentration/Emphasis

Emphasis: Medicinal Chemistry

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.