The therapeutic potential of novel cannabinoid receptors

Abstract

Cannabinoids produce a plethora of biological effects, including the modulation of neuronal activity through the activation of CB(1) receptors and of immune responses through the activation of CB(2) receptors. The selective targeting of either of these two receptor subtypes has clear therapeutic value. Recent evidence indicates that some of the cannabinomimetic effects previously thought to be produced through CB(1) and/or CB(2) receptors, be they on neuronal activity, on the vasculature tone or immune responses, still persist despite the pharmacological blockade or genetic ablation of CB(1) and/or CB(2) receptors. This suggests that additional cannabinoid and cannabinoid-like receptors exist. Here we will review this evidence in the context of their therapeutic value and discuss their true belonging to the endocannabinoid signaling system.

Figure 1. The structures of commonly used cannabinoids

The classical cannabinoids are Δ⁹-THC, cannabidiol, cannabinol and the synthetic cannabinoid HU-210. CP55,940 is the prototypical non-classical cannabinoid and WIN55,212-2 is the prototypical aminoalkylindole. AM251 and SR141716 are both used as CB₁ antagonists.

Figure 2. Phylogenetic tree analysis of GPCRs closely related to CB₁

Using the standard protein-protein BLAST (blastp) analysis, these related GPCRs share the highest amino acid sequence identities to CB₁.

Figure 3. Structures of endogenous and synthetic lipids

The endogenous cannabinoids anandamide (a) and 2-arachidonoyl glycerol (b). The putative endogenous ligand for GPR55, lysophosphatidylinositol (c). Lysophosphatidic acid (d), the endogenous lipid for LPA receptors. The endogenous lipids for S1P receptors sphingosine (e) and sphingosine-1-phosphate (f). The synthetic S1P receptor ligand FTY720 (g).