Medicinal Chemistry of Cannabis and Cannabinoids

As societal attitudes towards cannabis evolve along with our understanding of the endocannabinoid system, medical cannabis is poised to re-enter the mainstream pharmacopeia, especially in North America. Presently, significant gaps in knowledge exist regarding the true chemical composition of medical cannabis as well as the pharmacodynamics of cannabinoids and cannabis extracts. As such, deconvoluting the chemical complexity of cannabis is essential for maximizing its therapeutic benefits and reducing adverse effects in the clinic. Accordingly, this thesis presents a comprehensive investigation of cannabis and cannabinoids at the pre-clinical level, drawing on core aspects of medicinal chemistry and applying developed techniques under large study settings. Through pilot experiments, extraction protocols for the optimal recovery of cannabinoids from different types of cannabis plant material were investigated and the diverse phytochemistry of cannabis was revealed through extensive chemical profiling, reiterating the need for standardization and consistency in therapeutic-grade cannabis extracts. Meanwhile, receptor profiling at CB1 and CB2 receptors confirmed the importance of decarboxylation for the optimal biological activity of cannabinoids and cannabis extracts, demonstrating the suitability of microwave-assisted extraction for producing pharmacologically active cannabis extracts. Following this, high-level chemoinformatic analyses of receptor responses versus cannabinoid concentrations of cannabis extracts generated meaningful prediction models for CB1R and CB2R agonism, predicting the cannabinoid receptor activities of individual phytocannabinoids with reasonable accuracy and revealing differences in cannabinoid receptor responses between pure cannabinoids and cannabis extracts. Finally, the total synthesis and characterization of two pharmaceutically novel cis stereoisomers of CBD was undertaken, resulting in the first unambiguous identification of cis-CBD species and the isolation of a hitherto undescribed cis-Δ9-THC species. Through this thesis, we report significant real-world evidence for the case that cannabis and cannabis extracts behave as complex mixtures of physiologically active molecules, whereby their effects on receptors vary significantly with chemotype and in turn reflects their chemical compositions. Several first-in-kind studies detailed in this thesis pave the way for further investigations of cannabinoids into their chemical structures, mechanism(s) of receptor binding, as well as synergistic and antagonistic effects during co-administration that together bring about the unique and medically important effects of cannabis.

Department dc:contributor.department

Pharmaceutical Sciences

Year dc:date.issued

2023

Author dc:creator

• Yang, Yi

Advisor dc:contributor.advisor

• Kotra, Lakshmi P

• Analytical chemistry
• Cannabinoids
• Medical cannabis
• Medicinal chemistry
• Natural products
• Synthetic chemistry

Handle dc:identifier.uri

http://hdl.handle.net/1807/128282

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/128282