Introduction
This review covers the synthesis pathways and pharmacology of synthetic cannabinoid compounds. Synthetic cannabinoids are a class of novel psychoactive substances that act as agonists at cannabinoid receptors. This class of compounds is structurally diverse and rapidly changing, with multiple generations of molecules having been developed in the past decade. The structural diversity of synthetic cannabinoids is supported by the breadth of chemical space available for exploitation by clandestine chemists and incentivized by attempts to remain ahead of legal pressures.
What is synthetical cannabinoids
Cannabis contains a large number of compounds known as ‘cannabinoids’. These are produced naturally by the plant, and the most important is tetrahydrocannabinol, or THC. This is the major compound in cannabis responsible for the drug’s effects. The cannabinoids in cannabis target the cannabinoid receptors; these come in two varieties, CB1 and CB2 receptors. CB1 receptors are found primarily in the brain, and it’s the interaction of cannabinoids with these receptors that is responsible for psychological effects. The CB2 receptors are found mainly in the immune system, and are partly responsible for the anti-inflammatory and potential medicinal benefits of cannabis (though in some cases, these are also due to interaction with CB1 receptors).
Why do we even have receptors that the chemicals in cannabis are capable of activating? The cannabinoid receptors are usually activated by what are known as ‘endogenous cannabinoids’ – in other words, cannabinoid chemicals we produce in our bodies. One of these is anandamide, a neurotransmitter which has a number of roles, including in pain, appetite, and memory. Research into the roles of endogenous cannabinoids is still continuing – they were only discovered after investigation into the effects of THC in the body, hence why the class of chemicals and the receptors are named after cannabis.
Synthetic cannabinoids are a class of compounds originally synthesised to further investigate cannabinoid receptors, and the potential medicinal benefits of cannabis. None of them are found naturally in cannabis – they are all the product of laboratory synthesis. Work on them began in the 1970s, and initially, they were structurally similar to THC. However, since then, a wide variety of compounds with structures much different from that of THC have been synthesised. What they do all have in common is their interaction with cannabinoid receptors.
The manner in which the synthetic cannabinoids can be grouped is variable. Some studies place them in three very broad categories: classical cannabinoids, which are structurally similar to THC; aminoalkylindoles, the largest group, which can be split into further subcategories; and non-classical cannabinoids, which include compounds such as cyclohexylphenols. Other classification systems use seven or more groups, which are more structurally specific. The issue with the large number of new & different synthetic cannabinoids being produced for both research and illicit use is that in cases, they defy categorisation in some of these systems, which has led some researchers to suggest that they should instead be categorised by biological activity.
In terms of how they act, there are marginal differences between natural cannabinoids like THC and synthetic cannabinoids. Whilst they act on the same cannabinoid receptors, THC is only a partial agonist, whilst synthetic cannabinoids are full agonists. These terms will require a little explanation for those unfamiliar with them. An agonist is a molecule that binds to a receptor and activates it; a partial agonist does not induce the maximum response, however, whereas a full agonist can. The fact that synthetic cannabinoids are full agonists means that their potency compared to THC is higher; animal studies have suggested that their potency can be 2 to 100 times that of THC.
The first isolation of synthetic cannabinoids from ‘spice’ was reported in 2008, but reports of their use in ‘legal highs’ precede this. With cannabis classified as an illegal drug in many countries, these synthetic cannabinoids may seem an attractive substitute to many would-be cannabis smokers. The synthetic cannabinoids themselves are solids, but are dissolved in solvents then sprayed onto dried herbs, which can then be smoked.
Synthetic cannabinoids are a class of compounds originally synthesised to further investigate cannabinoid receptors, and the potential medicinal benefits of cannabis. None of them are found naturally in cannabis – they are all the product of laboratory synthesis. Work on them began in the 1970s, and initially, they were structurally similar to THC. However, since then, a wide variety of compounds with structures much different from that of THC have been synthesised. What they do all have in common is their interaction with cannabinoid receptors.
The manner in which the synthetic cannabinoids can be grouped is variable. Some studies place them in three very broad categories: classical cannabinoids, which are structurally similar to THC; aminoalkylindoles, the largest group, which can be split into further subcategories; and non-classical cannabinoids, which include compounds such as cyclohexylphenols. Other classification systems use seven or more groups, which are more structurally specific. The issue with the large number of new & different synthetic cannabinoids being produced for both research and illicit use is that in cases, they defy categorisation in some of these systems, which has led some researchers to suggest that they should instead be categorised by biological activity.
In terms of how they act, there are marginal differences between natural cannabinoids like THC and synthetic cannabinoids. Whilst they act on the same cannabinoid receptors, THC is only a partial agonist, whilst synthetic cannabinoids are full agonists. These terms will require a little explanation for those unfamiliar with them. An agonist is a molecule that binds to a receptor and activates it; a partial agonist does not induce the maximum response, however, whereas a full agonist can. The fact that synthetic cannabinoids are full agonists means that their potency compared to THC is higher; animal studies have suggested that their potency can be 2 to 100 times that of THC.
The first isolation of synthetic cannabinoids from ‘spice’ was reported in 2008, but reports of their use in ‘legal highs’ precede this. With cannabis classified as an illegal drug in many countries, these synthetic cannabinoids may seem an attractive substitute to many would-be cannabis smokers. The synthetic cannabinoids themselves are solids, but are dissolved in solvents then sprayed onto dried herbs, which can then be smoked.
Syntheses pathways
Most synthetic cannabinoids are synthesized according to the general principle: core + linked crop with linker + tail. The simplest example to understand is the synthesis of JWH-018: indole + 1-benzoyl chloride + 1-bromopentyl. Below is the synthesis scheme with groups, which are distinguished by colours.
Rather simple synthesis routes allow the construction of alternative synthetic cannabinoids with a certain affinity for CB1 receptors (CB1R).
General structural information of synthetic cannabinoids with JWH-018 as an example, where the dotted lines are connected bonds.
Moving to a separate portion of this alkylindole scaffold, compounds with methoxy, alkyl, and halogen substitutions around the naphthyl ring were tested. These analogues spurred the observation that additions to sterically hindered positions of the ring were not tolerated, whereas groups added to freely accessible positions were tolerated, and sometimes even improved activity. Multiple aromatic stacking interactions have also been observed in silico between high affinity CB1R ligands and the transmembrane domains 3−6 of CB1R, which is a region rich with tyrosine, phenylalanine, and tryptophan residues. Furthermore, several compounds used in these docking studies were JWH-series analogues which specifically lacked the carbonyl oxygen yet still retained CB1R activity, impugning a central tenet of the three-point theory, and supporting the π-stacking interpretation. However, this π-stacking CB1R agonist binding theory, which was sufficient to explain the affinity of naphthoylindole SCBs, was unable to explain the generations of SCBs that came to follow. Among these are the carboxamides in which the naphthoyl group is replaced by a nonaromatic derivative of valine. Many SAR studies were subsequently conducted to determine the effects of these broader scaffold changes on CB1R affinity, including substitution of the indole core for the closely related indazole, altering the valinamide side chain, changing a terminal carboxamide to a methyl ester, and fluorinating the terminal end of the N-alkyl chain. In support of this diversity-tolerant SAR, to date, there are hundreds of known SCB compounds identified from seized products, elucidating dozens of novel structural alterations that do not impair CB1R activity, while simultaneously being more difficult to detect. Following this expansion, easy structural generalization of SAR across all known SCBs has also become far more difficult. Nevertheless, based on the prototypical naphthoylindole SCBs, general SCB structures can be demarcated into four regions: a core, a head, a linker, and a tail.
The majority of seized SCBs in illicit products still contain indole or indazole cores, while common head groups consist of large aryl, hydrophobic groups, or valine derivatives. These two regions are linked most often by acyl, amide or ester bonds. Most tail groups are alkyl chains, especially pentyl varieties and their terminally fluorinated analogues, although cyclohexylmethyl and benzyl tail groups are also noteworthy. Overall, given the number of variations observed within each region for these known SCBs, tens- to hundreds-of-thousands of different combinatorial SCB molecules are conceivable, even considering limitations such as ease of synthesis, cost of precursors, and incompatibility of different moieties among the four regions. Therefore, there remains a great deal of chemical space available for SCBs that could plausibly be exploited in clandestine production.
Due to the impressive breadth of molecules that possess agonist activity at the CB1R, several synthetic routes to generate SCBs in a simple and cost-effective manner are available. Many of the most dominant routes derive from the work of John Huffman’s group in the study of CB1R SAR for naphthoyl-indole and -pyrrole containing compounds. As C3 is the primary site of electrophilic substitution on the indole core, naphthoylindoles were easily achieved through Friedel−Crafts acylation followed by N-alkylation. In contrast, acylation of the pyrrole core occurs at both C2 and C3: addition of an N-sulphonyl directing group, as well as solvent and temperature changes, are needed to achieve C3 selectivity. Both the synthetic complexity and reduced CB1R activity of the pyrrole SCBs justified prioritization of the naphthoylindole scaffold for future compound production. Over the years, this classic route has seen several variations for the generation of 3-acylindole SCBs, such as N-alkylation prior to 3-acylation and a microwave- assisted one-pot synthesis. As many of the newer generation SCBs contain amide and ester linkages between the core and head groups, slightly different approaches are required to synthesize these compounds. One of the easiest methods for generating these SCBs with the N-alkylation of 1H-indole. The reactivity of the indole C3 position allows the addition of trifluoroacetic anhydride to the crude N-alkylated product. The resulting 1-alkyl-3-trifluoroacetylindoles are subsequently hydrolyzed to the carboxylic acid. This acid can then be converted to an acid chloride or activated with standard coupling reagents; upon reaction with an amine or alcohol, the corresponding amide or ester linked indole SCBs, respectively, are produced. In contrast, amide and ester linked indazole analogues, which lack C3 reactivity, require use of a protected indazole-3-carboxylic acid, often as the methyl ester. Following N-alkylation, the acid can be deprotected, allowing the coupling of amines and alcohols as before. This discrepancy also accounts for the relative lack of acylindazole SCBs that have been identified, as Friedel−Crafts acylation of an indazole does not generally occur at C3, thus requiring additional modifications and adding additional complexity to the synthesis.
Examples
For examples of various synthetic cannabinoids which are synthesized according to the above pathways, compounds such as JWH-073, JWH-018, AM-2201, JWH-200, can be presented. Substituents on the indole ring (tails) was changed in this row, it changes their affinity for CB1R 12.9 ± 3.4 for JWH-073, 9.00 ± 5.00 nM for JWH-018, 1.0 nM for AM-2201 (with increasing potency).
In the row of ADBICA, PB-22, JWH-018, JWH-250 and UR-144 the attached groups are replaced (the naphthyl group of JWH-018 by others), it also changes their CB1R affinity 0.69 nM for ADBICA, 5.1 nM for PB-22, 9.00 ± 5.00 nM for JWH-018, 11.00 nM for JWH-250, 150 nM for UR-144 (with potency reduction).
Syntheses of various compounds take place under similar conditions with changes in reagents and loadings, which gives a wide opportunities for chemists.
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