Date of Award
Ph.D. in Pharmaceutical Sciences
Ikhlas A. Khan
Jordan K. Zjawiony
Kenneth J. Sufka
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.
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.