Date of Award
Spring 2026
Document Type
Open Access Dissertation
Department
College of Pharmacy
First Advisor
Juan Francisco León
Abstract
Cannabis sativa and phytocannabinoids have been utilized in medicine throughout human history, suggesting a clinical potential for cannabinoid derivatives. However, very few cannabinoid-based therapeutics have achieved regulatory approval, and this potential remains generally unrealized. This thesis explores the rational design and development of various cannabinoid derivatives (dimeric cannabinoids, aminergic cannabinoids, cannabinoid hydroxyquinones, cannabinoid chalcones, and psilocybin- cannabinoid hybrids) as therapeutics for diverse health conditions. Dimeric cannabinoids were designed as bitopic ligands for orthosteric-allosteric binding within the cannabinoid type 1 receptor. A library of cannabidiol/Δ8-tetrahydrocannabinol dimers displayed enhanced affinity toward serotonin 2B and sigma 2 receptors in radioligand binding assays, and partial agonism of cannabinoid type 1 receptors, suggesting utility as antiemetics or probes for investigating bitopic mechanisms. Aminergic cannabinoids were designed as neurological “magic shotguns”, capable of interacting with a series of key neurological receptors implicated in depressive conditions. Aminergic cannabinoids displayed enhanced affinity towards a series of serotonergic, adrenergic, dopaminergic, muscarinic, and sigma receptors, representing a significant improvement over the parent compound, cannabidiol. Notably, some aminergic cannabinoids displayed nanomolar affinity toward sigma 1 receptors and an ability to potentiate N-methyl-D-aspartate receptors in mouse primary hippocampal neurons, an effect that may be reversed in the presence of a selective sigma 1 receptor antagonist. Cell viability assays in SH-SY5Y cells revealed an effective therapeutic window for these aminergic cannabinoids, and these findings collectively suggest that these compounds may be useful antidepressants or neuroprotective agents. Other miscellaneous cannabinoid derivatives and their potential applications are briefly discussed. Altogether, these findings suggest there remains untapped clinical utility in the field of cannabinoid derivatives.
Rights
© 2026, Zachary Isaac Stryker
Recommended Citation
Stryker, Z. I.(2026). New Drugs From Old Roots: Reimagining Cannabinoid Scaffolds for Modern Therapeutics. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/8875