Our knowledge of the chemistry and biology of the endocannabinoids anandamide (AEA) and 2-AG is rapidly expanding with the discoveries of new biological roles, novel pharmacological targets and signaling pathways as well as enzymes responsible for their synthesis, hydrolysis, transport, and oxidative metabolism of these lipid mediators. As such, to explore the biological functions and pharmacology of the endocannabinoid system, metabolically stable analogs of AEA and 2-AG are needed. Incorporation of structural modifications to enhance the biological activities and target specificities of these lipids while increasing their metabolic stabilities, is a challenge. In our approach we explore two design principles: a) the introduction of chiral methyl groups and polar moieties at judiciously chosen positions within the arachidonoyl chain of the prototype, and b) the inclusion of steric bulk and stereochemistry in the vicinity of the hydrolysable head group of the lipid. Herein we report novel arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG) analogs that combine distinct conformational properties with unique functional profiles at the cannabinoid CB1 and CB2 receptors, coupled with enhanced stabilities for their respective deactivating enzymes. Unlike AEA and 2-AG, the novel endocannabinoid probes reported herein do not generate arachidonic acid which exhibits non-CB-mediated biological actions and in vitro and in vivo toxicity. 

Acknowledgements: Research supported by NIH/NIDA grants DA009158 and DA007215.