Molecular Targets of the Phytocannabinoids-A Complex Picture
Paula Morales, Dow P. Hurst, Patricia H. Reggio
Progress in the Chemistry of Organic Natural Products, 2017 ; 103: 103–131.
For centuries, hashish and marihuana, both derived from the Indian hemp Cannabis sativa L., have been used for their medicinal, as well as, their psychotropic effects. Phytocannabinoids are oxygen containing C21 aromatic hydrocarbons found in Cannabis sativa L. To date, over 120 phytocannabinoids have been isolated from Cannabis, including two compounds, (−)-trans-Δ9-tetrahydrocannabinol (Δ9-THC) and (−)-trans-Δ8-THC (Δ8-THC) that have been shown to bind to cannabinoid receptors and elicit the characteristic psychotropic effect associated with Cannabis . These compounds also have beneficial effects, such as appetite stimulation , analgesia , anti-glaucoma  and anti-emetic effects . Non-psychotropic phytocannabinoids are currently emerging as key constituents of Cannabis as well. For example, the non-psychotropic phytocannabinoid, CBD, is of great interest because of its anti-inflammatory, analgesic, anti-anxiety and anti-tumor properties . For many years, it was assumed that the beneficial effects of the cannabinoids were mediated by the cannabinoid receptors, CB1 and CB2. However, today we know that the picture is much more complex, with the same phytocannabinoid acting at multiple targets. This chapter focuses on the molecular pharmacology of the phytocannabinoids, including Δ9-THC and CBD, from the prospective of the targets at which these important compounds act.
2 Pharmacology of selected phytocannabinoids
To date over 120 cannabinoids, the so-called phytocannabinoids (pCB), have been isolated from the cannabis plant. Contrary to other naturally occurring drugs, such as opioids, nicotine, cocaine or caffeine, cannabinoids do not contain nitrogen, and hence are not alkaloids. Most phytocannabinoids share common structural features that include a dibenzopyran ring and a hydrophobic alkyl chain. The most abundant cannabinoids in the plant are Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydro-cannabinol (Δ8-THC), cannabinol (CBN), cannabidiol (CBD), cannabigerol (CBG), and cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV), cannabivarin (CBV),cannabidivarin (CBDV) (Figure 1). Despite their lower presence in the plant, other phytocannabinoids such as cannabinodiol (CBND), cannabielsion (CBE), cannabicyclol (CBL) and cannabitriol (CBT) have also been the subjects of study in the last decades (Figure 2) .
Phytocannabinoids show different affinities for CB1 and CB2 receptors. In addition, over the last years, molecular targets outside the endocannabinoid system have been identified for certain plant cannabinoids. These compounds have been shown to interact with other G-protein coupled receptors such as the putative cannabinoid receptors GPR55 or GPR18, and other well-known GPCRs such as the opioid or the serotonin receptors. In addition, several papers have reported the ability of certain phytocannabinoids to modulate nuclear receptors, ligand-gated ion channels or transient receptor potential (TRP) channels, among others.