Novel CB2 selective cannabinoids and inhibitors of endocannabinoid deactivation

Δ9-Tetrahydrocannabinol (Δ9-THC), a major psychoactive constituent of marijuana is known to exert a variety of pharmacological effects on laboratory animals and humans, through the activation of CB1 and CB2 receptors, which are considered attractive targets in the design of therapeutic agents. However, psychoactive effects and abuse potential have discouraged the therapeutic of use Δ9-THC in modern medicine. The deleterious effects of Δ9-THC have been correlated with direct CB1 activation. There are two possible approaches to eliminate these undesired effects. One approach is to design and synthesize high affinity ligands exhibiting CB2 receptor sub-type selectivity, thus eliminating direct CB1 activation. The second approach is by inhibiting rapid degradation of the major endogenous cannabinoids, N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), respectively, such that CB receptors may be indirectly stimulated through the enhanced levels of the endogenous compounds. Both of these methods have been investigated: (1) by pursuing structure-activity relationship (SAR) studies of bicyclic and tricyclic cannabinoids, biphenyl cannabinoids, and cannabilactones to explore the active site within the CB2 receptor, as well as designing and synthesizing CB2 selective covalent binding probes that may be used to map the receptor-binding site; and, (2) by pursuing the SAR studies of sulfonyl fluorides, biphenyltrifluoromethyl ketones, saccharinyl analogs, and &agr;-ketoheterocycles to explore the active site of the inhibitors of endocannabinoid deactivating proteins. ^ Binding affinities of ligands for rat CB1 and mouse CB2 were determined and selectivity evaluated. Further binding affinity studies on the cloned human CB2 were performed for ligands exhibiting high affinity in the mouse CB2 receptor assay. These studies have led to the development of high affinity ligands and have assisted our understanding the factors that lead to CB2 selectivity. In addition, IC50 values for novel inhibitors of the endocannabinoid deactivating proteins (FAAH and MGL) were determined and selectivity evaluated. This has led to the development FAAH selective inhibitors. These compounds will function as molecular probes to explore cannabiniod receptor action and may find use as therapeutic agents.