The Chemistry and Pharmacology of Synthetic Cannabinoid Receptor Agonists as New Psychoactive Substances: Origins

Synthetic cannabinoid receptor agonists (SCRAs) have proliferated as new psychoactive substances (NPS) over the past decade. Relative to other classes of NPS, SCRAs are structurally heterogeneous; however, most SCRAs act as potent, high-efficacy agonists of cannabinoid type 1 and type 2 receptors (CB1 and CB2, respectively). Characterization of the pharmacology and toxicology of these substances is hindered by the dynamic nature of the SCRA marketplace. Beyond basic pharmacological profiling at CB1 and CB2 receptors, very little is known about the acute or chronic effects of SCRAs. Many of the effects of SCRAs are qualitatively similar to those of the Δ9-tetrahydrocannabinol (Δ9-THC) found in cannabis. However, unlike Δ9-THC, SCRAs are frequently associated with serious adverse effects, including cardiotoxicity, nephrotoxicity, and death. This chapter will provide an overview of the structure and function of the primary target for SCRAs, the CB1 receptor, and survey the structure-activity relationships of the historical SCRAs that served as templates for the earliest generations of NPS.