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

Abstract

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.

Adolescent Cannabinoid and Nicotine Exposure Differentially Alters Adult Nicotine Self-Administration in Males and Females

“…Finally, in these studies, we examined the effects of an injected cannabinoid agonist during adolescent development on nicotine self-administration in adulthood. Importantly, these results have direct implications for the use of 'spice' synthetic cannabinoids, of which the majority belong to the aminoalkylindole (AAI) class, including WIN 55,212-2 [7][8][9] . In addition, these findings likely have further implications for cannabis exposure.…”

“…Nicotine, the main psychoactive component in tobacco and e-cigarettes, acts in the brain on neuronal nicotinic acetylcholine receptors (nAChRs), and the psychoactive effects of cannabis have been attributed to action on the cannabinoid 1 receptor (CB1R). The CB1Rs are also targeted by other abused drug, such as synthetic 'spice' cannabinoid agonists for which the majority belong to the aminoalkylindole class, including WIN55-212,2 [7][8][9] . The nAChRs and CB1Rs exhibit overlapping expression patterns within brain regions implicated in drug reinforcement and aversion, including the prefrontal cortex, ventral tegmental area, nucleus accumbens, medial habenula, interpeduncular nucleus and hippocampus 10,11 .…”

Synthetic cannabinoid receptor agonists: Analytical profiles and development of QMPSB, QMMSB, QMPCB, 2F‐QMPSB, QMiPSB, and SGT‐233

“…Since the initial discovery of pravadoline and WIN 55,212-2 in the late 1980s and their subsequent identification as cannabinoid receptor agonists in the mid-1990s, 1,2 several thousand synthetic cannabinoid receptor agonists (SCRAs) of the same basic "tail-corelinker-head" chemotype 3,4 have been reported. Reviews in this field (eg, Huffman and Padgett, 5 Manera et al, 6 Wiley et al, 7 Banister and Connor, 8,9 and Alam and Keating 10 ) indicate that many of these substances originated within university settings for pharmacological research into cannabinoid receptors and their downstream signaling systems.…”

The endocannabinoid system – current implications for drug development

“…The prototypical CB receptor ligand is of course THC, which acts as a partial agonist at CB 1 and CB 2 receptors [ 37 ]. This differs from the synthetic compounds such as 5F CUMYL‐PICA and MDMB‐FUBINACA and MDMB‐CHIMICA which have been rationally designed as recreational drugs [ 38 ] and which generally have greater efficacy than THC [ 38 , 39 , 40 ]. This difference in efficacy, together with potential off‐target effects of the compounds per se and/or their metabolites and impurities in the preparations, accounts for the more severe adverse effects of such compounds, including ‘zombie‐like’ behaviours, hallucinations, neurological disturbances and possibly even death [ 41 , 42 , 43 ].…”