Biaryl ligands as probes for proteins of the endocannabinoid system

Date of Completion

January 2005


Chemistry, Organic|Chemistry, Pharmaceutical




The objective of this research was to explore the versatility of the biaryl pharmacophore in the discovery of novel high affinity ligands for probing the proteins of the endocannabinoid system. The lipophilic biaryl moiety was used as a molecular template for the design and synthesis of several series of cannabinergic agents. This structure-activity relationship study has led to the design of selective probes for the five major proteins of the endocannabinoid system including the CB1 and CB2 receptors, the anandamide transporter (AT), fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The development of these high affinity probes is leading to a better understanding of the biochemistry and pharmacology of the endocannabinoid system, and is directed at the discovery of new cannabinoid-based therapeutic agents. ^ A broad array of functional groups has been employed as substituents for the aromatic rings of the biaryl core. This has led to a wide variety of biaryl derivatives that were capable of interacting as ligands with the proteins of the endocannabinoid system. While many of the biaryl ligands interacted with all five major proteins of the endocannabinoid system, this structure-activity relationship study allowed us to establish selective profiles for some of the target proteins. Although a few ligands exhibited high affinity for the CBI receptor or selective inhibition of monoacylglycerol lipase over fatty acid amide hydrolase, the major focus of this research was to identify biaryl ligands with stronger interactions with the CB2 receptor relative to the other proteins of endocannabinoid system. Some biaryl ligands were found to have high affinities for the CB2 receptor and very good CB2 selectivity. In addition, some success has been achieved in addressing the challenge of probing the structural differences of CB2 receptors across species. These new biaryl ligands with high affinity and selectivity for human CB2 receptor (hCB2) are promising candidates for future development. ^ Some CB2 selective biaryl compounds that have been tested in vivo were found to have potent peripheral antinociceptive effects without CNS side effects. Further explorations of biaryl-based CB2 selective ligands, as well as biaryl-based selective ligands for the other proteins of the endocannabinoid system, have the potential to develop novel therapeutic cannabimimetic agents without CNS side effects. ^