Minor Cannabinoids: Biosynthesis, Molecular Pharmacology and Potential Therapeutic Uses

Abstract

The medicinal use of Cannabis sativa L. can be traced back thousands of years to ancient China and Egypt. While marijuana has recently shown promise in managing chronic pain and nausea, scientific investigation of cannabis has been restricted due its classification as a schedule 1 controlled substance. A major breakthrough in understanding the pharmacology of cannabis came with the isolation and characterization of the phytocannabinoids trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This was followed by the cloning of the cannabinoid CB1 and CB2 receptors in the 1990s and the subsequent discovery of the endocannabinoid system. In addition to the major phytocannabinoids, Δ9-THC and CBD, cannabis produces over 120 other cannabinoids that are referred to as minor and/or rare cannabinoids. These cannabinoids are produced in smaller amounts in the plant and are derived along with Δ9-THC and CBD from the parent cannabinoid cannabigerolic acid (CBGA). While our current knowledge of minor cannabinoid pharmacology is incomplete, studies demonstrate that they act as agonists and antagonists at multiple targets including CB1 and CB2 receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), serotonin 5-HT1a receptors and others. The resulting activation of multiple cell signaling pathways, combined with their putative synergistic activity, provides a mechanistic basis for their therapeutic actions. Initial clinical reports suggest that these cannabinoids may have potential benefits in the treatment of neuropathic pain, neurodegenerative diseases, epilepsy, cancer and skin disorders. This review focuses on the molecular pharmacology of the minor cannabinoids and highlights some important therapeutic uses of the compounds.

Anti-Microbial Activity of Phytocannabinoids and Endocannabinoids in the Light of Their Physiological and Pathophysiological Roles

“…Apart from exerting anti-microbial activities, which will be discussed in more detail below (Section 3.3), phytocannabinoids modulate several physiological and pathophysiological processes in humans and other mammalians, making them potential therapeutic drugs in various settings [12][13][14]31,[111][112][113][114][115]. Among others, these compounds have been shown to have anti-inflammatory, anti-oxidative, anti-nausea, anti-nociceptive, anti-convulsant, anti-neoplastic, anxiolytic, and neuroprotective properties [14,111,112,[114][115][116][117]. Cannabinoids also affect cognition, such as learning and memory, consciousness, and emotion, including anxiety and depression [118,119].…”

“…Cannabinoids also affect cognition, such as learning and memory, consciousness, and emotion, including anxiety and depression [118,119]. Some cannabinoid-based drugs (e.g., Marinol, Syndros, Cesamet, Sativex, and Epidiolex) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of epilepsy, Dravet syndrome, Lennox-Gastaut syndrome, Parkinson's disease, spasticity associated with multiple sclerosis, neuropathic pain, mental illnesses, chemotherapy-induced nausea, and AIDS wasting syndrome [117,[120][121][122]. Marinol and Syndros contain the (-)-trans-∆ 9 -THC dronabinol; Cesamet contains the synthetic cannabinoid nabilone that shows structural similarities to ∆ 9 -THC; and Epidiolex contains CBD.…”

“…CBG activates TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, 5-HT 1a receptor, α2-adrenergic receptor, and PPARγ, while being a TRPM8 antagonist [210][211][212][213][214][215]. CBG has anti-inflammatory, anti-oxidative, and anti-nociceptive activities [117,209,213,216]. The anti-inflammatory property is thought to be achieved by modulating the CB2 receptor, TRP channels, and PPARγ, and by inhibiting cyclooxygenase 1 and 2 (COX-1/2) [210,211,217], while the analgesic effect of CBG is thought to be mediated through the α2-adrenergic receptor [211].…”

“…CBGA displays low affinity for both CB1 and CB2 receptors but causes a similar decrease in intracellular cAMP levels as ∆ 9 -THC [229]. Since CBGA can activate PPARs [212], it is expected to affect lipid metabolism [117]. A Cannabis sativa cultivar containing high levels of CBG and CBGA inhibited the activity of the aldose reductase enzyme, which catalyzes the reduction of glucose to sorbitol [239].…”

“…CBN is formed during the degradation of ∆ 9 -THC and has a lower binding affinity to CB1 and CB2 receptors than ∆ 9 -THC [117]. CBN is an agonist of the TRPV1, TRPV2, TRPV3, TRPV4, and TRPA1 cation channels [210].…”