Molecular Targets of the Phytocannabinoids: A Complex Picture

Abstract

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. These effects are associated with the phytocannabinoids which are oxygen containing C₂₁ aromatic hydrocarbons found in Cannabis sativa L. To date, over 120 phytocannabinoids have been isolated from Cannabis. For many years, it was assumed that the beneficial effects of the phytocannabinoids 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 contribution 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.

Keywords: CB1 receptor; CB2 receptor; CBC; CBD; CBDV; CBE; CBG; CBL; CBN; CBND; CBT; CBV; GPCR; Glycine receptor; PPARγ; Phytocannabinoid; THCV; TRPA1 channel; TRPM8 channel; TRPV1 channel; Δ8-THC; Δ9-THC.

Fig. 1

Structures of most abundant phytocannabinoids in Cannabis sativa L.

Fig. 2

Structures of phytocannabinoids in lower abundance.

Fig. 3

(A) The typical Class A G-protein coupled receptor structure is illustrated here by the 2.8 Å structure of the mu opioid receptor (MOR; PDB entry 4DKL) (B) An extracellular view of the MOR structure is illustrated here. In MOR, the extracellular loops of the receptor are splayed open, making ligand access from the extracellular milieu possible. Here the covalent ligand, beta-funaltrexamine is bound.

Fig. 3

(A) The typical Class A G-protein coupled receptor structure is illustrated here by the 2.8 Å structure of the mu opioid receptor (MOR; PDB entry 4DKL) (B) An extracellular view of the MOR structure is illustrated here. In MOR, the extracellular loops of the receptor are splayed open, making ligand access from the extracellular milieu possible. Here the covalent ligand, beta-funaltrexamine is bound.

Fig. 4

The 2.8 Å structure of the S1P1 receptor is illustrated here (PDB 3V2Y with antagonist, ML056). In this receptor, the N-terminus covers the EC side of the receptor, permitting no ligand access from the EC milieu. Instead, there is a portal between THH1 and TMH7 that allows ligand access from the lipid bilayer.

Fig. 5

This figure shows results from molecular dynamics simulations in which the CB endogenous ligand, 2-AG enters the CB2 receptor from the lipid bilayer via a TMH6–TMH7 portal.

Fig. 6

Potential mechanisms of PPAR-phytocannabinoids interactions: A) Direct binding of phytocannabinoids to these nuclear receptors; B) Possible conversion of phytocannabinoids into metabolites that may activate PPARs; C) Phytocannabinoid transported to the nucleus by FABPs; D) Another possibility is that phytocannabinoids modulate CBR triggering intracellular signalling pathways that may lead to the activation of PPARs.

Fig. 7

The 2.8 Å structure of PPARγ with ajulemic acid is illustrated here (PDB 2OM9).

Fig. 8

Structure of glycine receptors: pentamers formed by α and β subunits in a ratio of 2α:3β [116], each subunit consists of four transmembrane segments, the second transmembrane helix of each subunit forms the lining of the ion pore of these ligand-gated ion channels.

Fig. 9

General structure of the TRP channels modulated by phytocannabinoids: TRPV, TRPM and TRPA.

Fig. 10

The 3.27 Å structure of the TRPV1 channel is illustrated here.