Exceptionally Potent Chiral Anandamide Analogs

Abstract

We recently reported an innovative design approach that allowed us to obtain potent endocannabinoids with enhanced metabolic stability. Our design is characterized by the incorporation of chiral centers within the endocannabinoid prototypes N-arachidonoylethanolamide and 2-arachidonoylglycerol. Work on N-arachidonoylethanolamide led to the identification of the first-generation lead analog (R)-N-(1-Methyl-2-hydroxyethyl)-13-(S)-methyl-arachidonamide (AMG315). Here, we synthesized a series of tail-modified AMG315 analogs to further optimize this novel chemotype for cannabinoid receptor binding affinity and potency. Our advanced molecule, namely, 20,20,20-trifluoro-(R)-N-(1-methyl-2-hydroxyethyl)-13-(S)-methyl-arachidonamide (AM12814, 12), is the first endocannabinoid analogue exhibiting unprecedented affinity for both the CB1 and CB2 receptors. In further in vitro functional characterization, 12 behaves as a potent, partial CB1 and CB2 agonist. Our SAR results are supported by docking studies of 12 on the crystal structures of cannabinoid receptors, while when tested in vivo, 12 behaves as a very potent and efficacious CB1 agonist. This analogue will serve as a unique endocannabinoid probe.