In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa

Abstract

The Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆9-tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆9-THC is known to bring about the ‘high’ associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆9-THC, ∆9-tetrahydrocannabinolic acid (∆9-THCa), ∆9-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, βarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.

Cannabis sativa: Interdisciplinary Strategies and Avenues for Medical and Commercial Progression Outside of CBD and THC

“…THCV also antagonised anandamide and methanandamide in mice vas deferens, attenuating stimulated contractile responses [309]. More recently, THCV was shown to similarly displace CP55,940 from CB 1 and CB 2 in CHO cells, and contrary to previous assumptions, was shown to be a weak partial CB 1 agonist at high doses [179]. Moreover, Zagzoog et al [310] showed THCV to produce anxiolytic, hypothermic, anti-nociceptive, hypolocomotive, and cataleptic effects in vivo in mice.…”

“…Parkinson's disease Murine models [181] Pain, anxiety, hypothermia, catalepsy Murine models [179] WIN55,212-2 Prostate cancer in vitro human [190] WIN55,212-2, JWH-133 Breast, lung cancer in vitro human [191,192]…”

“…CBG has shown partial agonism of CB 1 and CB 2 , α 2 -adrenceptor agonism and 5-HT 1A antagonism, while exerting some minor anti-nociceptive and anxiolytic properties in vivo [179,333]. Mice models of inflammatory bowel disease (IBD) showed positive outcomes with CBG treatment including reductions in the level of reactive oxygen species in intestinal cells, as well as reduced nitric oxide concentration in macrophages through CB 2 modulation [194].…”

In Silico and In Vitro Analysis of Major Cannabis-Derived Compounds as Fatty Acid Amide Hydrolase Inhibitors

“…Of them, Δ 9 -tetrahydrocannabinol (THC) is the main psychoactive ingredient [ 2 ]. Additional cannabinoids with biological activity are cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), Δ 9 -tetrahydrocannabivarin (THCV) and cannabigerol (CBG) [ 4 , 5 ], all shown in Figure 1 a.…”

“…To date, several studies have interrogated the effects of cannabis-derived compounds on the major eCB-binding receptors [ 4 , 5 ], whereas little is known on their potential interaction with rFAAH [ 46 ] or hFAAH [ 47 ]. Here, we sought to fill this gap by investigating the potential interaction of some relevant cannabis-derived compounds with both enzymes, through the combination of in silico computational analysis and in vitro activity assays.…”