Cannabinoid receptors: nomenclature and pharmacological principles

Abstract

The CB1 and CB2 cannabinoid receptors are members of the G protein-coupled receptor (GPCR) family that are pharmacologically well defined. However, the discovery of additional sites of action for endocannabinoids as well as synthetic cannabinoid compounds suggests the existence of additional cannabinoid receptors. Here we review this evidence, as well as the current nomenclature for classifying a target as a cannabinoid receptor. Basic pharmacological definitions, principles and experimental conditions are discussed in order to place in context the mechanisms underlying cannabinoid receptor activation. Constitutive (agonist-independent) activity is observed with the overexpression of many GPCRs, including cannabinoid receptors. Allosteric modulators can alter the pharmacological responses of cannabinoid receptors. The complex molecular architecture of each of the cannabinoid receptors allows for a single receptor to recognize multiple classes of compounds and produce an array of distinct downstream effects. Natural polymorphisms and alternative splice variants may also contribute to their pharmacological diversity. As our knowledge of the distinct differences grows, we may be able to target select receptor conformations and their corresponding pharmacological responses. Importantly, the basic biology of the endocannabinoid system will continue to be revealed by ongoing investigations.

Figure 1

The structures of prototypical cannabinoid compounds from each structural class.

Figure 2

Schematic of G Protein Coupled Receptor (GPCR). Panel A. Depiction of inactive receptor (left) and agonist-activated receptor (right). In the inactive state, the G protein-GDP bound subunit complex is bound to the receptor protein (left); whereas upon binding of agonist at the orthosteric site, the receptor is activated and the G protein subunits βγ dissociate from the GTP bound α subunit (right). Panel B illustrates binding of either competitive antagonist or negative allosteric modulator at orthosteric and allosteric sites respectively. Note that the receptor is not activated by either of these ligands. Panel C. Binding of a positive allosteric modulator, at an allosteric site. Note that this ligand does not activate the receptor in and of itself. Panel D. Constitutive activity is demonstrated on the left. The receptor is in an activated state, bound to the α subunit of the GDP-G protein complex, in the absence of agonist. Presumably in this state the receptor conformation is different than the agonist-receptor conformation, indicated by a difference in receptor shape and shading. Binding of an inverse agonist, at the orthosteric site of a constitutively active receptor causes a “disactivation” of constitutive activity, a presumed conformational change, and re-coupling of the G-protein subunits with the receptor. Note that the position of the G protein complex is shown bound to the receptor in a slightly different location to illustrate a different G protein-receptor conformational state, accommodating decreased basal activity consequent to inverse agonist binding.

Figure 3

Concentration-response analysis with agonists illustrating full and partial agonists. Shown are a full agonist WIN 55,212-2 (■), a potent, partial agonist CP 55,940 (▲), and a less potent partial agonist anandamide (O). (Data adapted from McAllister et al, 1999).

Figure 4

Concentration-response curves with competitive and non-competitive antagonists present. Shown are the concentration-response curves for an agonist CP55,940 (●) in the absence of antagonist, in the presence of a competitive antagonist SR141716A (■) and in the presence of a functional non-competitive antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl] urea (PSNCBAM-1) (▲).

Figure 5

Representation of a concentration-response curve from an inverse agonist. Inverse agonism produced by SR141716A is concentration-dependent and opposite of the effect produced by an agonist.