AM-11638

We report the development of novel endocannabinoid analogs carrying phenyl rings in judiciously chosen positions within the tetraolefinic chain pharmacophore of the endogenous N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG). Key successful analogs were found to exhibit remarkably high binding affinity and potency for cannabinoid receptors. Importantly, among the reported SAR studies of endocannabinoids, as well as mono- and poly unsaturated fatty acid derivatives, the current work is the first to show that the nonconjugated Z double bonds of a polyunsaturated fatty acid signaling molecule can be replaced by phenyl rings, the most common framework in marketed drugs. Our SAR results are supported by docking studies of the key analogs on the crystal structures of CB1 and CB2 receptors. When tested in vivo, our key analog AM11638 behaves as a more potent and longer lasting analgesic than the endogenous anandamide. Stereoselective procedures for the demanding syntheses of the new analogs are described.