Date of Award
1-1-2017
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
Department
Biomolecular Sciences
First Advisor
Ikhlas A. Khan
Second Advisor
Jordan K. Zjawiony
Third Advisor
Kenneth J. Sufka
Relational Format
dissertation/thesis
Abstract
The field of salvinorin chemistry represents a novel and emerging field of opioid research. The novelty is derived from the lead pharmacophore: salvinorin A — a neoclerodane diterpenoid natural product isolated from Salvia divinorum. Salvinorin A represents a pharmacologically unique compound in that it is the first known non-nitrogenous KOR subtype-selective agonist, exhibits a comparatively safe physiological profile with no reports of toxicological effects in clinical trials, and, most importantly, has a steadily growing body of literature indicating potentially useful clinical applications (e.g. antinociceptive, anti-addictive, antipruritic, neuroprotective, etc.). This has encouraged the development of analogues as essential molecular probes to elucidate the structure-activity-relationship of the salvinorin-class.
In this study, we expand the current field of salvinorin chemistry through the design, development, and preclinical evaluation of a series of C(22)-fused heteroaromatic salvinorin A analogues. Our in vitro models include: opioid receptor competitive radioligand binding affinity and functional [35S]GTP[γS] binding activity assays; while our in vivo models include: antinociceptive, antidepressant, and anxiolytic related assays. This resulted in three analogues exhibiting EC50 sub-200 nM functional activity, of which two displayed antinociceptive activities, with one also demonstrating antidepressant-like activity. As such, this study further supports the importance of the continued development of new salvinorin A analogues as essential research tools to ascertain potential three-dimensional ligand binding requirements, functional activities, and pharmacological consequences mediated through the clinically important opioid receptors.
Recommended Citation
Keasling, Adam, "Molecular Characterization of the Opioid Receptors: Design, Development, and Preclinical Evaluation of Salvinorin A-Based Molecular Probes." (2017). Electronic Theses and Dissertations. 1472.
https://egrove.olemiss.edu/etd/1472