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Synthetic cannabinoids are a class of designer drug molecules that bind to the same receptors to which cannabinoids (THC, CBD and many others) in cannabis plants attach. These novel psychoactive substances should not be confused with synthetic phytocannabinoids (THC or CBD obtained by chemical synthesis) or synthetic endocannabinoids from which they are in many aspects distinct. Typically, synthetic cannabinoids are sprayed onto plant matter and are usually smoked, although they have also been ingested as a concentrated liquid form in the US (United States) and UK (United Kingdom) since 2016. They have been marketed as herbal incense, or "herbal smoking blends", and sold under common names like K2, spice, and synthetic marijuana. They are often labeled "not for human consumption" for liability defense. A large and complex variety of synthetic cannabinoids are designed in an attempt to avoid legal restrictions on cannabis, making synthetic cannabinoids designer drugs. Most synthetic cannabinoids are agonists of the cannabinoid receptors. They have been designed to be similar to THC, the natural cannabinoid with the strongest binding affinity to the CB1 receptor, which is linked to the psychoactive effects or "high" of marijuana. These synthetic analogs often have greater binding affinity and greater potency to the CB1 receptors. There are several synthetic cannabinoid families (e.g. AM-xxx, , HU-xx, JWH-xxx) which are classified by the creator of the substance (e.g. JWH stands for John W. Huffman), which can include several substances with different base structures such as classical cannabinoids and unrelated naphthoylindoles. Synthetic marijuana compounds began to be manufactured and sold in the early 2000s. From 2008 to 2014, 142 synthetic cannabinoid receptor agonists were reported to the European Monitoring-Center for Drugs and Drug Addiction (EMCDDA). Reported user negative effects include palpitations, paranoia, intense anxiety, nausea, vomiting, confusion, poor coordination, and seizures.

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Structure-activity relationships of synthetic cannabinoid designer drug RCS-4 and its regioisomers and C4 homologues

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RCS-4 [(4-methoxyphenyl)-1-yl-(1-pentyl-1H-indol-3-yl)methanone] represents the first of several N-alkyl-3-(methoxybenzoyl)indoles identified by forensic scientists as synthetic cannabinoid (SC) designer drugs. Despite the detection of RCS-4 and several analogues (RCS-2, RCS-3, RCS-2-C4, RCS-3-C4, and RCS-4-C4) in products intended for human consumption, relatively little is known about this class of cannabinoids. The synthesis of all regioisomers of RCS-4 and their C4 homologues is described. This study also systematically explored the structure-activity relationships of this class of SCs at human CB1 and CB2 receptors using an in vitro fluorometric imaging plate reader membrane potential assay. All compounds demonstrated agonist activity at CB1 (EC50 = 54-574 nM) and CB2 (EC50 = 4.5-46 nM) receptors, with the C4 homologues showing a preference for CB2 receptors over CB1 receptors (31-42 times). Since most of the analogues (RCS-2, RCS-3, RCS-2-C4, RCS-3-C4 and RCS-4-C4) are not subject to regulation in much of the world, despite their activities towards CB1 and CB2 receptors, there is a possibility that these analogues will emerge on the black market.

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