Novel endocannabinoid analogs

Cannabinoid receptor type 1 and 2 (CB1 and CB2) are two Gi/o-protein-coupled cannabinoid receptors (CBRs), which showed promise in various conditions including pain, inflammation, CNS disorders, and cancer. 2-Arachidonoylglycerol (2-AG) and N-arachidonoylethanol amine (AEA) are well-recognized and characterized endogenous ligands for CB1 and CB2. However, due to their low chemical and biochemical stability, it is relatively difficult to use these two endogenous ligands directly, to probe their biological role(s), and to explore the functions of cannabinoid receptors and enzymes. In most tissues, 2-AG and AEA are metabolized by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) respectively. 2-AG can also be deactivated by esterases such as the brain hydrolase ABHD6. Moreover, recent studies have demonstrated that oxidative enzymes including cyclooxygenase-2 (COX-2), cytochrome P450, and lipoxygenases (LOXs) can transform endocannabinoids into eicosanoid-related bioactive products. Here, we are reporting novel analogs with enhanced bioactivities at CB receptors and increased stabilities to the actions of hydrolytic and/or oxidative enzymes.In this dissertation, detailed Structure-Activity Relationship (SAR) studies on endocannabinoid scaffold to improve enzymatic stability, potency and efficacy were described. All four pharmacophoric regions of the prototype, namely: 1) the head group, 2) the methylene linker, 3) the tetraolefinic chain, and 4) the n-pentyl tail, were explored and led to the discovery of several novel endocannabinoid analogs with unique functional groups, improved potency and/or metabolic stability. Further investigations using these novel probes developed during my study will enhance our understanding of the role of endocannabinoids in the whole endocannabinoid system (ECS).--Author's abstract