Date of Award

Summer 2024

Document Type

Open Access Dissertation

Department

College of Pharmacy

First Advisor

Michael Wyatt

Second Advisor

Campbell McInnes

Abstract

Synthetic cannabinoid receptor agonists (SCRA), also referred to as synthetic cannabinoids (SCs), pose a significant public health risk, create an undue burden on local emergency departments, and present significant challenges for law enforcement officers and forensic laboratories. SCs are a diverse group of compounds sold with the intent to illicit psychoactive responses like tetrahydrocannabinol (THC), the primary psychoactive component in marijuana. Since their initial detection in 2004, illicit use of SCs has grown in popularity. Recognizing the dangers of SC use, the Drug Enforcement Agency has moved to schedule the analytes routinely identified in street drugs. Despite these efforts, the deluge of illicit SCs entering the country has not slowed as distributors switch to analytes not currently scheduled. There is a severe lack of structure-based toxicological and pharmacological data associated with SC use, which hampers clinicians treating suspected SC adverse exposure cases. There is an urgent need to describe the mechanism of actions associated with SC exposures and the scope of side effects during adverse drug reactions to SCs. In this research, I pursued a comprehensive structure-function study of structurally diverse SCs to generate a consensus pharmacophore model of binding to cannabinoid receptors, with the intent to inform selection of compounds for further study of their genotoxicity and cytotoxicity. We hypothesize that a structure-function study of SCs will provide a consensus pharmacophore model which, coupled with in vitro testing, will inform identification of SC toxicophores. Chapter 1 provides historical context and current challenges related to cannabinoid use and abuse. Chapter 2 provides an evaluation of THC like dibenzopyrans to generate a comprehensive structure activity relationship (SAR) and pharmacophore information using ligand and structure based computational chemistry. Chapter 3 provides experimental results which demonstrate exposure to select SCs at typical physiological concentrations cause DNA damage and reduces cell viability in mammalian breast cancer cells used as a model due to their expression of CB1 receptors. Collectively, the information found herein will serve as an important platform that can ultimately help health care providers, law enforcement, and guide public policy makers to make informed decisions related to treatment, enforcement and drug scheduling.

Rights

© 2024, Robert Michael Sears

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