The main goal in the study of the structure-activity relationship (SAR) of cannabis-derived compounds for the cannabinoid receptors is understanding the receptor binding sites. Currently, only the crystal structure of the human cannabinoid receptor CB1 has been fully achieved [63
]. Deciphering the SAR of phytocannabinoids may help further understand the pharmacology and medicinal chemistry of the cannabinoid receptors in order to develop targeted remedies [64
]. Moreover, understanding the SAR mechanisms of cannabinoids with their receptors may help the clinical research find new substances with therapeutic effects [65
] and with minimized side-effects on cognitive functions.
Over the past 60 years, considerable research in medicinal chemistry has been carried out towards the SAR development of the natural classical cannabinoids; only in 1986 did the research group of R. K. Razdan analyze the SAR of about 300 cannabinoid analogues based on their activity in different animal models [66
]. After the identification of Δ9
-THC in 1964 [67
], several chemical modifications of the side chain and/or the tricyclic scaffold led to the characterization of families of potent selective ligands that could be involved in the activation of the main cannabinoid receptor. It has been shown that the n
-pentyl chain at the C-(3) position (Figure 1
), incorporated during the biosynthesis of olivetolic acid [49
], represents the key pharmacophoric group of THC [68
] and modification in this side chain leads to critical changes in the affinity, selectivity and pharmaco-potency of these ligands relating to the cannabinoid receptors (Figure 2
In general, a shorter chained alkyl group reduces the potency of the compound to interact with the receptor. In THC, for example, a propyl group at C-(3) creates THCV (tetrahydrocannabivarine), which shows a 75% reduction in the potency to CB1 [66
]. An increase in the number of carbon atoms (hexyl, heptyl, or octyl) leads to a respective increase in affinity and potency to interact with the cannabinoid receptors [70
]. The length of the C-(3)-side chain of THC directly corresponds with CB1 and CB2 binding affinities, as an increase in chain length leads to an increase in binding affinity with the cannabinoid receptors [70
]. Based on these ideas, various analogues of different carbon chains and rings, with or without heteroatom incorporation, may suggest the prediction of a SAR profile for a given structure, such as the THC scaffold. Besides the well-established study of the candidate target of SAR modulation based on the alkyl side chain, a number of other transformations in the tricyclic core of the cannabinoid structure have been carried out [72
]. The cannabinoid compounds resulting from the pyran ring-opening reaction belong to the cannabidiol (CBD) derivatives, which demonstrate relatively low affinity to the CB1/CB2 cannabinoid receptors along with low psycho-activity [73
]. Early SAR studies showed that the pyran ring in the cannabinoidic structure was not a requirement for cannabinergic activity in animal assays. However, several cannabidiol derivatives with high affinities for CB1 and CB2 receptors have been synthesized and thoroughly investigated [58
]. Another possible structure modification on the THC scaffold is the C-(1) phenol group (Figure 1
). THC analogues that lack the phenolic hydroxyl group altogether, or even those exhibiting minor modifications to their phenolic group, may demonstrate drastic changes in their pharmacological abilities. It was recognized that CBD derivatives that experienced etherification or elimination of the phenol group displayed significant selectivity for CB2. The C-(11) methyl group is another major pharmacophore where minor structural changes can significantly modulate receptor binding (Figure 2
). Substitutions at this position do not confer selectivity when compared to analogues modified at the C-(1) phenol; however, the binding affinity may be greatly enhanced by this modification.
-THC is an agonist for both CB1 and CB2 receptors. Its analgesic properties [74
] were often overlooked due to its psychotropic side effects resulting from its activation of the CB1 receptor. This has limited the clinical application of the cannabinoid dual agonists, despite the multiple potential benefits for the treatment of neurodegenerative diseases, among others [75
]. Therefore, the potential of synthesized cannabinoid analogues that may exploit the therapeutic effects of cannabinoids without evoking the non-desired psychotropic properties is highly desired and extensive research in this direction is underway.