Major Phytocannabinoids and Their Related Compounds: Should We Only Search for Drugs That Act on Cannabinoid Receptors?

Abstract

The most important discoveries in pharmacology, such as certain classes of analgesics or chemotherapeutics, started from natural extracts which have been found to have effects in traditional medicine. Cannabis, traditionally used in Asia for the treatment of pain, nausea, spasms, sleep, depression, and low appetite, is still a good candidate for the development of new compounds. If initially all attention was directed to the endocannabinoid system, recent studies suggest that many of the clinically proven effects are based on an intrinsic chain of mechanisms that do not necessarily involve only cannabinoid receptors. Recent research has shown that major phytocannabinoids and their derivatives also interact with non-cannabinoid receptors such as vanilloid receptor 1, transient receptor ankyrin 1 potential, peroxisome proliferator-activated receptor-gamma or glitazone receptor, G55 protein-coupled receptor, and nuclear receptor, producing pharmacological effects in diseases such as Alzheimer's, epilepsy, depression, neuropathic pain, cancer, and diabetes. Nonetheless, further studies are needed to elucidate the precise mechanisms of these compounds. Structure modulation of phytocannabinoids, in order to improve pharmacological effects, should not be limited to the exploration of cannabinoid receptors, and it should target other courses of action discovered through recent research.

Keywords: cannabidiol; cannabigerol; cannabinoid receptors; endocannabinoid system; pharmacology; phytocannabinoids; synthetic cannabinoids; tetrahydrocannabinol.

Figure 1

Chemical structures and binding affinities of ten major phytocannabinoids able to cause, in vitro, the displacement of synthetic [³H]CP55940 bound to human cannabinoid receptors 1 or 2 both embedded in cellular membranes. The binding affinities are reported according to the published data available in the following scientific articles: ^a [65]; ^b [70]; ^c [68].The chemical structures were prepared with ACD/ChemSketch, and the three classes of phytocannabinoids are included in separate inserts. The substituents of the resorcinyl moiety whose replacements cause a change in affinity constants (Ki) are highlighted.

Figure 2

Chemical structures of CBG derivatives VCE-003 and VCE-003.2.

Figure 3

Chemical structure of CBDA derivative HU-580.