The Chemistry and Pharmacology of Synthetic Cannabinoid Receptor Agonists as New Psychoactive Substances : Origins, Samuel D. Banister and Mark Connor, 2018

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

Samuel D. Banister and Mark Connor

Handbook of Experimental Pharmacology, # Springer International Publishing AG, part of Springer Nature 2018

doi : 10.1007/164_2018_143



1 Introduction
2 Chemical Classification of Synthetic Cannabinoid Receptor Agonists
3 Cannabinoid Type 1 Receptor (CB1) Structure and Function
4 Historical Synthetic Cannabinoid Receptor Agonists
4.1 Classical Cannabinoids and Phytocannabinoid Analogs
4.2 Nonclassical Cannabinoids
4.3 Aminoalkylindoles (AAIs)
5 Synthetic Cannabinoid Receptor Agonists as New Psychoactive Substances
5.1 Molecular Hybridization
5.2 Bioisosteric Fluorination
6 Conclusions


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.

Keywords : Anandamide · Cannabinoid · CP 55,940 · JWH-018 · NPS ·Δ9-Tetrahydrocannabinol · WIN 55,212-2 · XLR-11


1 Introduction

Since the first conclusive identification of synthetic cannabinoid receptor agonists (SCRAs) as new psychoactive substances (NPS) in 2008, more than 230 SCRA NPS have been reported in 106 countries in all regions of the world (UNODC 2017). SCRA raw materials are most commonly manufactured in China, imported to the country of sale by organized crime groups or entrepreneurs, and applied to dried
plant matter for use as smoking blends with superficial similarity to cannabis. The first SCRA NPS were detected in herbal blends packaged in foil sachets and disingenuously marketed as “incense,” “potpourri,” “air freshener,” and “not for human consumption.” The first confirmed SCRA NPS product was branded “Spice,” a reference to the fictional narcotic drug of the same name in Frank Herbert’s science fiction novel Dune. Many other SCRA NPS products have appeared since, branded with names like K2 and Black Mamba, although Spice has remained a generic term for SCRA NPS. Like the branded packaging, the SCRA constituents of these products change rapidly in response to legislative controls, with little consistency between products (Dresen et al. 2010). Less commonly, SCRAs are sold as bulk
powders of high purity, as liquid formulations for vaporization in electronic cigarettes, blended into a dough-like substance as “fake hash,” and in edible products such as candy and baked goods (Peace et al. 2017; Obafemi et al. 2015; Angerer et al. 2015; EMCDDA 2017).

SCRAs represent the largest and most structurally diverse class of NPS. However, like the principal psychoactive component of cannabis, ()-trans-Δ9-tetrahydrocannabinol (Δ9-THC, 1, Fig. 1), all are intended to elicit psychoactive effects by activating cannabinoid type 1 receptors in the brain. Unlike cannabis, SCRAs are frequently associated with serious adverse effects, including death (Trecki et al.
2015). The differing toxicological profiles of SCRAs and Δ9-THC are attributed to differences of chemical structure, metabolism, and pharmacology. The first generation of SCRA NPS were repurposed compounds sourced directly from published academic research and patents, but by 2010 new structures with no precedent in the scientific literature were appearing.

The proliferation of SCRAs and other NPS in the Internet age can be viewed as a consequence of (1) the democratization of medicinal chemistry knowledge, (2) inexpensive and accessible chemical manufacturing by contract research organizations (CROs) in China and elsewhere, (3) the response of retailers to constantly changing legislation domestically and internationally, and (4) an inability for traditional legislative procedures to keep pace with a sudden and dramatic increase in the number of recreational drugs not under international control. The chemical complexity and dynamic nature of the SCRA market presents an ongoing challenge for medical professionals, law enforcement officers, and policymakers across the globe. The current chapter will describe the chemistry and pharmacology
of historical SCRAs developed prior to their discovery as NPS, and the subsequent chapter will review the structural evolution of emergent SCRAs identified in the 2010s.

2 Chemical Classification of Synthetic Cannabinoid Receptor Agonists

The term cannabinoid is broad and refers to a specific class of compounds produced by the cannabis plant (phytocannabinoids produced by Cannabis sativa and Cannabis indica), as well as endogenous and exogenous ligands that interact with cannabinoid type 1 and type 2 receptors (CB1 and CB2, respectively). Endogenous cannabinoids (endocannabinoids) are lipid-signaling molecules structurally distinct from phytocannabinoids. Synthetic cannabinoid receptor agonists comprise several distinct chemotypes, some of which are structurally related to phyto- and endocannabinoids (Fig. 1). Several structurally unique natural products that act as CB1 and CB2 agonists in vitro have been identified in plants other than cannabis; however, none have been identified as NPS (Gertsch et al. 2010; Russo 2016).

The cannabis plant has been cultivated by humans for thousands of years as a source of textiles, food, and herbal medicine, and the use of cannabis flowers and leaves as recreational substances has been reported since antiquity (Zuardi 2006). Cannabis contains more than 560 chemical constituents, of which a class of approximately 120 terpenoids are unique to cannabis and are named phytocannabinoids (ElSohly et al. 2017; Turner et al. 2017). The most abundant phytocannabinoids obtained from cannabis are Δ9-THC and non-psychoactive ()-cannabidiol (CBD, 2). Other minor phytocannabinoids, including cannabinol (CBN, 3) and cannabinodiol (CBND, 4), are also psychoactive but are found in cannabis at
concentrations likely insufficient to contribute to psychoactivity. In addition to being listed in Schedule I, cannabis was placed in the strictest category (Schedule IV) of the United Nations 1961 Single Convention on Narcotic Drug and remains the most widely used illicit drug today.

The structural elucidation of Δ9-THC as the psychoactive component of cannabis occurred in 1964 (Gaoni and Mechoulam 1964). The mammalian target responsible for the activity of Δ9-THC, a class A G protein-coupled receptor (GPCR), was cloned from rat brain in 1990 (rCB1) (Matsuda et al. 1990). Shortly thereafter, human CB1 (hCB1) was cloned and demonstrated 97% sequence identity at the amino acid level with rCB1 (Gérard et al. 1991). An endogenous eicosanoid ligand for CB1, N-arachidonoyl-ethanolamide (AEA, 5), was isolated from pig brain in 1992 and named anandamide from the Sanskrit word for bliss (Devane et al. 1992). A second cannabinoid receptor subtype (CB2) was discovered in macrophages in 1993 (Munro et al. 1993) and a second endocannabinoid, 2-arachidonoylglycerol (2-AG,
6), from canine gut in 1995 (Mechoulam et al. 1995). Oleamide (7) is an endogenous ligand that was also shown to act as a selective CB1 agonist (Leggett et al. 2004). CB1 and CB2 are extensively characterized receptors of an endocannabinoid system (ECS) and differ in distribution, ligand selectivity, and function (Howlett et al. 2002; Mackie 2008). Several orphan and recently deorphanized GPCRs have been proposed as putative members of the ECS based on their interaction with cannabinoid ligands; however, these receptors typically show little sequence homology with CB1 and CB2 (Pertwee et al. 2010; Morales and Reggio 2017). Other components of the ECS include cellular machinery involved in the biosynthesis, metabolism, and transport of endocannabinoids, and have seldom been targeted by NPS manufacturers (Piomelli 2003; Di Marzo 2008).