CB2 Receptor Ligands

The CB1 receptor is found principally in the central nervous system and is responsible for the overt physiological effects of cannabinoids. In contrast, the CB2 receptor is expressed primarily in the immune system and is responsible for few, if any, obvious behavioral effects. Although many cannabinoid receptor ligands show little, or at best modest, selectivity for either receptor, a number of synthetic compounds are known which have significant selectivity for the CB2 receptor. These include cannabimimetic indoles, such as 1-propyl-2-methyl-3-(1-naphthoyl)indole (JWH-015) and 1-(2,3-dichlorobenzoyl)-2-methyl-3-(2-[1-morpholino] ethyl)-5-methoxyindole (L768242), both of which have good affinity for the CB2 receptor, but weak affinity for the CB1 receptor. Efforts have been made to develop structure-activity relationships (SAR) at CB2 for cannabimimetic indoles, but with limited success. Several derivatives of traditional dibenzopyran based cannabinoids have also been found to have significant selectivity for the CB2 receptor. These include 1- methoxyΔ8-THC derivatives, 1-methoxyΔ8-THC-DMH (L759633), 1-methoxyΔ9(11)-THC-DMH (L759656), and 1-methoxy-3-(1',1'-dimethylhexyl)Δ8-THC (JWH-229), plus a number of 1-deoxyΔ8-THC analogues. In particular, 1-deoxy-3-(1',1'-dimethylbutyl)Δ8-THC (JWH-133) shows two hundred-fold selectivity for the CB2 receptor. Very recently several compounds belonging to other structural groups have also shown selectivity for the CB2 receptor. This review will describe the current status of the results of these studies and discuss the SAR for these classes of ligands.