Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists

Abstract

It is widely accepted that non-endogenous compounds that target CB(1) and/or CB(2) receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with Delta(9)-tetrahydrocannabinol or nabilone, both CB(1)/CB(2) receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB(2)-selective agonists, peripherally restricted CB(1)/CB(2) receptor agonists and CB(1)/CB(2) antagonists and inverse agonists as medicines. Already, numerous cannabinoid receptor ligands have been developed and their interactions with CB(1) and CB(2) receptors well characterized. This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB(1), non- CB(2) G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner. It begins with a brief description of how each of these ligands interacts with CB(1) and/or CB(2) receptors.

Fig. (1)

The structures of the CB₁/CB₂ cannabinoid receptor agonists, (−)-Δ⁹-tetrahydrocannabinol [(−)-Δ⁹-THC], HU-210, CP55940, R-(+)-WIN55212, anandamide and 2-arachidonoyl glycerol.

Fig. (2)

The structures of ACEA, ACPA, methanandamide and noladin ether, each of which activates CB₁ receptors more potently than CB₂ receptors.

Fig. (3)

The structures of JWH-133, HU-308, JWH-015 and AM1241, each of which activates CB₂ receptors more potently than CB₁ receptors.

Fig. (4)

The structures of the cannabinoid CB₁ receptor antagonists/inverse agonists, rimonabant, AM251, AM281, LY320135 and taranabant, each of which blocks CB₁ receptors more potently than CB₂ receptors.

Fig. (5)

The structures of the cannabinoid CB₂ receptor antagonists/inverse agonists, SR144528 and AM630, both of which block CB₂ receptors more potently than CB₁ receptors.