Novel Tetraolefinic Chain Phenyl Substituted Endocannabinoid Probes

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.