New metabolically stable fatty acid amide ligands of cannabinoid receptors: Synthesis and receptor affinity studies

We investigated the structure–activity relationships for the interactions of fatty acid amide analogs of the endocannabinoid anandamide with human recombinant cannabinoid receptors. Thirty-five novel fatty acid amides were synthesized using five different types of acyl chains and 11 different aromatic amine ‘heads.’ Although none of the new compounds was a more potent ligand than anandamide, we identified three amine groups capable of improving the metabolic stability of arachidonoylamides and their CB1/CB2 selectivity ratio to over 20-fold, and several aromatic amines capable of improving the affinity of short chain or monosaturated fatty acids for cannabinoid CB1 receptors. For the first time a tertiary amide of arachidonic acid was found to possess moderate affinity (Ki = 300 nM) for cannabinoid CB1, but not CB2, receptors.

Graphical abstractThirty-five novel stable fatty acid amide ligands selective for cannabinoid CB1 receptors are reported, including some tertiary amides of arachidonic acid.Figure optionsDownload full-size imageDownload as PowerPoint slide