Adding more “spice” to the pot: A review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists

Synthetic cannabinoid receptor agonists (SCRAs) first appeared on the international recreational drug market in the early 2000s in the form of SCRA‐containing herbal blends. Due to the cannabimimetic effects associated with the consumption of SCRAs, they have acquired an ill‐informed reputation for being cheap, safe, and legal alternatives to illicit cannabis. Possessing high potency and affinity for the human cannabinoid receptor subtype‐1 (CB1) and ‐2 (CB2), it is now understood that the recreational use of SCRAs can have severe adverse health consequences. The major public health problem arising from SCRA use has pressed legislators around the world to employ various control strategies to curb their recreational use. To circumvent legislative control measures, SCRA manufacturers have created a wide range of SCRA analogs that contain, more recently, previously unencountered azaindole, γ‐carbolinone, or carbazole heterocyclic scaffolds. At present, little information is available regarding the chemical syntheses of these newly emerging classes of SCRA, from a clandestine perspective. When compared with previous generations of indole‐ and indazole‐type SCRAs, current research suggests that many of these heterocyclic SCRA analogs maintain high affinity and efficacy at both CB1 and CB2 but largely evade legislative control. This review highlights the importance of continued research in the field of SCRA chemistry and pharmacology, as recreational SCRA use remains a global public health issue and represents a serious control challenge for law enforcement agencies. A review of the chemistry and pharmacology of newly emerging azaindole‐, γ‐carboline‐, and carbazole‐type synthetic cannabinoid receptor agonists.