Abstract
Synthetic cannabinoid receptor agonists (SCRAs) are a chemically diverse class of compounds originally designed to explore the therapeutic benefits of the endocannabinoid system. The compounds have gained considerable attention owing to their ability to mimic the psychoactive effects of Δ9-tetrahydrocannabinol (THC), the primary bioactive component of cannabis, instigating their diversion to the recreational drug market. However, SCRA use is increasingly associated with incidences of severe toxicity and death worldwide, with limited insight into their pharmacology or toxicology. SCRAs are predicted to mediate their effects primarily through activation of the cannabinoid CB1 receptor (CB1). Yet characterisation of the molecular pharmacology at CB1 has failed to reveal a unique activity profile pertaining to SCRAs, aside from their potent and efficacious activation of the receptor. This thesis aimed to further characterise the molecular pharmacology of SCRAs beyond CB1, focusing on the cannabinoid CB2 receptor (CB2) and potential ‘off-target’ receptors.
Preliminary hypotheses surrounding SCRA toxicity implicated the robust recruitment of β-arrestins, proteins fundamental to the regulation of G protein-coupled receptors (GPCRs), such as the cannabinoid receptors. In this thesis, G protein-coupled receptor kinases (GRKs), enzymes considered crucial to facilitating receptor interactions with β-arrestins, were dispensable in the translocation of β-arrestins to CB2, contrary to the classical paradigm proposed for GPCRs. Subsequent characterisation of several signalling and regulatory pathways revealed SCRAs induced robust activation of CB2, contrasting with the activity profile of THC, most notably in the translocation of β-arrestins – congruent with findings at CB1. Finally, investigation into the activation of non-cannabinoid GPCRs failed to support the proposition that off-target activity partly mediates the complex and extensive physiological effects of SCRAs.
The findings in this thesis corroborated that SCRAs induce robust activation of the cannabinoid receptors, with limited off-target activity. However, this thesis fails to identify a molecular mechanism underlying SCRA-mediated toxicity. Further research is required to elucidate whether the activation of CB2 contributes to the physiological effects of SCRAs. Advancing our understanding of the pharmacology of this diverse class of compounds remains vital to identifying potential links to toxicity and predicting harm in humans.