International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂

Abstract

There are at least two types of cannabinoid receptors (CB(1) and CB(2)). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ(9)-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB(1), non-CB(2) established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB(1) and/or CB(2) receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel "CB(3)" cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB(1), non-CB(2) pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB(3) receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB(1) receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB(1)/CB(2) receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB(1), non-CB(2) cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.

Fig. 1.

The structures of (−)-Δ⁹-tetrahydrocannabinol [(−)-Δ⁹-THC], HU-210, CP55940, R-(+)-WIN55212, anandamide, and 2-AG.

Fig. 2.

The structures of the CB₁-selective agonists ACEA, arachidonylcyclopropylamide (ACPA), methanandamide, and noladin ether and of the CB₂-selective agonists JWH-133, HU-308, JWH-015, and AM1241.

Fig. 3.

The structures of the CB₁-selective antagonists/inverse agonists, rimonabant, AM251, AM281, LY320135, and taranabant and of the CB₂-selective antagonists/inverse agonists SR144528 and AM630.

Fig. 4.

The structures of NESS O327 and O-2050.

Fig. 5.

The structures of (−)-11-hydroxy-Δ⁸-tetrahydrocannabinol, ajulemic acid, cannabinol, cannabidiol, abnormal-cannabidiol, O-1602, cannabigerol, virodhamine, and N-arachidonoyl dopamine.

Fig. 6.

Neighbor joining tree showing relationships between the human cannabinoid CB₁ and CB₂ receptors and other human rhodopsin α-group type G protein-coupled receptors. The tree was generated using the multiple sequence alignment program ClustalX, with bootstrapping (1000 bootstrap trials), and viewed using NJ plot. The tree shows receptors that are discussed in section IV.A of this review; the muscarinic acetylcholine receptors M₁–M₅ are included as an outgroup.

Fig. 7.

Neighbor joining tree showing relationships between human GPR55 and other human rhodopsin δ-group type G protein-coupled receptors. The tree was generated using the multiple sequence alignment program ClustalX, with bootstrapping (1000 bootstrap trials), and viewed using NJ plot. The tree shows receptors that are discussed in section IV.B of this review.