Cannabinoid ligands, receptors and enzymes: Pharmacological tools and therapeutic potential

Abstract

Endocannabinoids have been identified to have roles in numerous physiological and pathological processes. Largely due to the association of the effects of Cannabis administration on mental states, the CNS impact of the endocannabinoid system has been the most intensively studied. Here, we provide a brief summary of the endocannabinoid system, comprising the receptors and the multiple endogenous lipid derivatives which activate them, as well as the enzymes which control the levels of these lipid derivatives. We identify pharmacological tools which may be used to interrogate the endocannabinoid system, as well as current and future options to exploit the system in the clinic.

Keywords: 2-arachidonoylglycerol; Cannabis; anandamide; cannabinoids; the endocannabinoid system.

Figure 1.

Structures of some endogenous, plant-derived and synthetic cannabinoids. From the top left, clockwise: AEA: anandamide (also known as N-arachidonoylethanolamine); THC: Δ⁹-tetrahydrocannabinol; 2AG: 2-arachidonoylglycerol; JWH133; CP55940; metAEA: R-methanandamide. In the centre of the figure is WIN, WIN55212-2.

Figure 2.

Selectivity of some endogenous, plant-derived and synthetic cannabinoids. Illustrated are calculated occupancies of CB₁ and CB₂ cannabinoid receptors expressed as a % of total at ligand concentrations of 100 nM. Indicated are groups of endocannabinoids, AEA and 2AG (Felder et al., 1995; Mechoulam et al., 1995), CB₁-selective agonists, ACEA (N-arachidonoyl-2’-chloroethylamine) and methanandamide (Hillard et al., 1999; Lin et al., 1998), non-selective agonists, THC, CP55940, HU210, WIN55212-2 (Felder et al., 1995; Showalter et al., 1996), CB₂-selective agonists, JWH133, JWH015 and HU308 (Hanus et al., 1999; Huffman et al., 1999; Showalter et al., 1996).

Figure 3.

Structures of CB₁- (AM251 and rimonabant) and CB₂-selective (AM630 and SR144528) antagonists.

Figure 4.

Selectivity of cannabinoid antagonists. Illustrated are calculated occupancies of CB₁ and CB₂ cannabinoid receptors expressed as a % of total at ligand concentrations of 100 nM. Indicated are three CB₁-selective antagonists, rimonabant, AM251 and LY320135 (Felder et al., 1995, 1998; Lan et al., 1999) and two CB₂-selective antagonists, AM630 and SR144528 (Rinaldi-Carmona et al., 1998; Ross et al., 1999).

Figure 5.

A schematic overview of the endogenous cannabinoid system. Illustrated are the three major phases of endocannabinoid turnover: synthesis, hydrolysis and transformation. The two major synthetic enzymes are diacylglycerol lipase (DAGL) and N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD). 2-Arachidonoylglycerol (2AG) hydrolysis may be mediated via monoacylglycerol lipase (MAGL), αβ hydrolase 12 (ABHD12) or αβ hydrolase 6 (ABHD6). In parallel, anandamide (AEA) can be hydrolysed by fatty acid amide hydrolase (FAAH), FAAH2 or N-acylethanolamine acid amidase (NAAA). Both 2AG and AEA can be transformed into apparently independently bioactive metabolites through cyclooxygenase-2 (COX-2), lipoxygenase (LOX) or epoxygenase/cytochrome P450 (EPOX/CYP).