CB1 and CB2 receptors are two cannabinoid receptors and belong to the big family of Gi/o-protein-coupled receptors. They are being pursued as potential targets for conditions including pain, inflammation, CNS disorders, and cancer. 2-arachidonoyl glycerol (2-AG) and <i>N</i>-arachidonoylethanolamine (AEA) are the two most-recognized endogenous ligands for cannabinoid receptors. However, due to their chemical and biochemical instabilities, it is relatively difficult to use endocannabinoids directly to probe its biological role and to explore the bioactivities of related receptors and enzymes. In most tissues, 2-AG and AEA can be metabolized by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) respectively. Other enzymes like a brain hydrolase (ABHD6) can also inactivate endocannabinoids. 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 developing novel analogs with enhanced bio-activities at CB receptors and increased stabilities to the actions of hydrolytic and/or oxidative enzymes. Towards this end, currently, we are exploring the head group of 2-AG and AEA with special emphasis on the ester moiety and the methylene linker. Our design focuses on the reverse ester and amide design approach and the incorporation of steric features at the methylene linker of the endogenous prototype.<br/>

Design and synthesis of metabolically stable endocannabinoid analogs by reversing ester and amide group

2019 Spring National Meeting

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