Overview of Non-CB1/CB2 Cannabinoid Receptors: Chemistry and Modeling

Abstract

To date, two cannabinoid receptors, CB1R and CB2R, have been isolated by molecular cloning. The CB1R and CB2R cannabinoid receptors are Class A G protein-coupled receptors (GPCRs) that bind constituents of Cannabis sativa, such as the classical cannabinoid agonist (−)-trans-delta-9-tetrahydrocannabinol [(−)-Δ9-THC (1)]. CB1R and CB2R bind four other structural classes of ligands (see Fig. 2.1): nonclassical cannabinoid agonists typified by 2-[5-Hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-5-(1-methyl-heptyl)-phenol (CP55,940 (2)), endogenous cannabinoids typified by N-arachidonoylethanolamine (anandamide, AEA (3)) and sn-2-arachidonoylglycerol (2-AG, (4)) (Biochem Pharmacol 50(1):83–90, 1995), aminoalkylindole (AAI) agonists typified by (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpho-linylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2 (5)), and biarylpyrazole antagonists typified by N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A (6)) and 1-(2,4-Dichloro-phenyl)-5-(4-iodo-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (AM251 (7)). A large number of physiological processes are controlled by the endogenous cannabinoids (Cannabinoids, Handbook of experimental pharmacology, Springer, Berlin, 2005). Most of these effects have been attributed to action at either the cannabinoid CB1R or CB2R receptors. Yet there are effects that clearly are not CB1R- or CB2R-mediated. Some of these cannabinoid effects may in fact not be receptor mediated at all. However, there is mounting evidence that suggests the involvement of additional GPCRs in cannabinoid effects, as well as the involvement of transient receptor potential (TRP) channels, such as the TRPV1 channel, and peroxisome proliferator-activated receptors. This chapter examines the chemistry of compounds at GPCRs for which a strong link with the other cannabinoid receptors (CB1R and CB2R) has been made. Open image in new window Fig. 2.1 The structures illustrated here are CB1R/CB2R ligands