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A closer look at cannabimimetic terpenes, polyphenols, and flavonoids: a promising road forward#br#
Juliana Cavalli, Rafael Cypriano Dutra
2021, 16 (7):
1433-1435.
doi: 10.4103/1673-5374.301011
Despite the current interest in the potential medical use of Cannabis, it is worth remembering that cannabis is not a new drug, with both a nonmedical and medical history supporting its effectiveness. This history advanced in scientific strength and importance worldwide when Professor Raphael Mechoulam and colleagues initiated their pioneering discoveries in 1971. At first, Mechoulam et al. (1972) achieved the complete synthesis of the pure compounds from hashish (including ∆1-tetrahydrocannabinol and other neutral cannabinoids such as cannabigerol, cannabichromene, and cannabicyclol), and established their molecular structures. This set a strong pace for the study of their structure-activity relationship and started to pave a promising road of discovery! Later on, the most important compounds were isolated and identified, namely ∆9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), and cannabinol, which represent some of the main tools used in preclinical and clinical research in the cannabinoid field. The endocannabinoid system (ECS) was proposed with the discovery of the endocannabinoids anandamide and 2-arachidonoylglycerol. With further progress in research, it became clear that the functions of the endocannabinoid signaling system are not limited to the brain, but are exerted throughout the organism. It has been proposed that endocannabinoids are released from cells as soon as their biosynthesis ends, avoiding release via secretory vesicles. Their actions on receptors are locally restricted, possibly due to their high lipophilicity and rapid inactivation under physiological conditions. In this scenario, the former would determine the promiscuity of cannabinoids in terms of their actions on different molecular targets, while the latter would affect the levels of cannabinoids since they are under the influence of biosynthesis and degradative enzymes. Both endocannabinoid compounds have been shown to mimic some effects of synthetic cannabinoids on their G-protein coupled receptors (CB1R and CB2R) and metabolizing enzymes. The G-protein coupled receptors CB1R (cloned in 1990) and CB2R (cloned in 1993) exhibit 48% similarity in their amino acid sequences. These receptors have been shown to exhibit particular differences in signaling mechanisms, tissue distribution and sensitivity to agonists and antagonists that depict marked binding selectivity between both receptors. When CBR is activated, adenylate cyclase is inhibited provoking the conversion inhibition of ATP to cyclic AMP. CB1R and CB2R located at peripheral, spinal, or supraspinal sites are important targets, mediating the effects of cannabinoids via the inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pain pathway, and reductions in neuroinflammatory signaling (Starowicz and Finn, 2017). Other receptors have been reported to be activated by cannabinoid drugs and related molecules, including GPR55, GPR18, and GPR119. However, the CB1R has been considered a key component of the ECS since it is the most abundant metabotropic receptor in the brain and interacts with endogenous and exogenous cannabinoids, including ∆9-THC. Furthermore, there is a large body of evidence to demonstrate that CB1R and CB2R, as well as their ligands, play a significant role in physiological and pathological processes. Therefore, changes in endocannabinoids anandamide and 2-arachidonoylglycerol concentration, as well as activation or deactivation of both CBRs in the tissues have been widely studied, as they can be relevant for the modulation of neurological and neurodegenerative diseases, neuroinflammation, cancer, immune-mediated inflammatory diseases, and autoimmunity (Di Marzo, 2008).
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