Exploring structure-activity relationships of synthetic cannabinoid receptor agonists

Abstract

New psychoactive substances (NPS) are synthetic alternatives to traditional drugs of abuse that have arisen due to international control. Synthetic cannabinoid receptor agonists (SCRAs), which make up 31% of the 1230 individual NPS reported since 2013, pharmacologically emulate Δ9-tetrahydrocannabinol (Δ9-THC), the primary intoxicant found in cannabis. SCRAs are characterised by their high potency and efficacy at cannabinoid receptor 1 (CB1), which is part of the endogenous cannabinoid (endocannabinoid) system. SCRAs are often considerably more efficacious than Δ9-THC, a factor that is theorised to play a role in their increased toxicological burden. Multiple mass poisoning events have been linked to SCRA exposure, and as such SCRAs represent a significant public health challenge. Like other NPS, clandestine manufacturers of SCRAs seek to exploit gaps in legislation to manufacture and sell these substances as “legal high” products. This has produced notable structural variation in SCRA chemical composition, with manufacturers employing modern medicinal chemistry techniques to modify existing illicit SCRA scaffolds to evade legislative controls while attempting to retain desired biological activity. Chemical and pharmacological characterisation of emerging SCRAs is therefore crucial for public health bodies, legislators, and law enforcement to respond to the array of issues related to SCRA use. This thesis is centred around the proactive synthesis, characterisation, and pharmacological evaluation of novel SCRAs, and related prophetic analogues. Investigation of structure-activity relationships (SARs) of these compounds allows for increased expanded understanding of the chemical space around a given SCRA and provides insight as to what compounds may or may not appear and linger in the international NPS marketplace.