Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products

Abstract

Cannabinoid receptors (CB1 and CB2), as part of the endocannabinoid system, play a critical role in numerous human physiological and pathological conditions. Thus, considerable efforts have been made to develop ligands for CB1 and CB2, resulting in hundreds of phyto- and synthetic cannabinoids which have shown varying affinities relevant for the treatment of various diseases. However, only a few of these ligands are clinically used. Recently, more detailed structural information for cannabinoid receptors was revealed thanks to the powerfulness of cryo-electron microscopy, which now can accelerate structure-based drug discovery. At the same time, novel peptide-type cannabinoids from animal sources have arrived at the scene, with their potential in vivo therapeutic effects in relation to cannabinoid receptors. From a natural products perspective, it is expected that more novel cannabinoids will be discovered and forecasted as promising drug leads from diverse natural sources and species, such as animal venoms which constitute a true pharmacopeia of toxins modulating diverse targets, including voltage- and ligand-gated ion channels, G protein-coupled receptors such as CB1 and CB2, with astonishing affinity and selectivity. Therefore, it is believed that discovering novel cannabinoids starting from studying the biodiversity of the species living on planet earth is an uncharted territory.

Cannabis: A Toxin-Producing Plant with Potential Therapeutic Uses

“…Exogenous THC is a partial CB1 and CB2 agonist, while phytocannabinoid CBD has a low affinity for these receptors [ 29 , 30 ]. Recently, two phytocannabinoids were discovered and isolated from Cannabis sativa : Δ9-tetrahydrocannabiphorol (Δ9-THCP, (13), Figure 1 ), a Δ9-THC homolog that binds with high affinity to both CB1 and CB2, and cannabidiphorol (CBDP, (14), Figure 1 ), a CBD homolog that has no available reports on its pharmacological effects yet [ 31 ]. For the binding mode of some of the mentioned compounds with cannabinoid receptors type 1 (CB1) and type 2 (CB2), please see Figure 3 .…”

Molecular Mechanism of Cannabinoids in Cancer Progression

“…The best known CB2-selective antagonists/inverse agonists are diarylpyrazole (SR144528) and 6-iodopravadoline (AM-630) [87]. These compounds have been used as CB2 receptor antagonists; however, some studies report the ability of SR144528 to inhibit breast cancer cells proliferation by acting as a agonist [88].…”

Functional Fine-Tuning of Metabolic Pathways by the Endocannabinoid System—Implications for Health and Disease

“…These results increase the prospects that CB1R blockade may still be a viable option to combat dysmetabolism and may move to clinical testing in the future [ 104 ]. The clinical studies with CB1 agonists, partial agonists, inverse agonists and neutral antagonists clearly point out the CB1R as a potential effective target for the treatment of obesity [ 2 , 102 , 105 , 106 , 107 ]. Another way of modulating CB1R activity is represented by compounds that could be developed by studying recently identified endogenous allosteric inhibitors of CB1R.…”