Analogues and homologues of N-palmitoylethanolamide, a putative endogenous CB2 cannabinoid, as potential ligands for the cannabinoid receptors

The presence of CB2 receptors was reported in the rat basophilic cell line RBL-2H3 and N-palmitoylethanolamide was proposed as an endogenous, potent agonist of this receptor. We synthesized a series of 10 N-palmitoylethanolamide homologues and analogues, varying by the elongation of the fatty acid chain from caproyl to stearoyl and by the nature of the amide substituent, respectively, and evaluated the affinity of these compounds to cannabinoid receptors in the rat spleen, RBL-2H3 cells and CHO-CB1 and CHO-CB2 receptor-transfected cells. In rat spleen slices, CB2 receptors were the predominant form of the cannabinoid receptors. No binding of [H-3]SR141716A was observed. [H-3]CP-55,940 binding was displaced by WIN 55,212-2 and anandamide. No displacement of [H-3]CP-55,940 or [H-3]WIN 55,212-2 by palmitoylethanolamide derivatives was observed in rat spleen slices. In RBL-2H3 cells, no binding of [H-3]CP-55,940 or [H-3]WIN 55,212-2 could be observed and conversely, no inhibitory activity of N-palmitoylethanolamide derivatives and analogues was measurable. These compounds do not recognize the human CB1 and CB2 receptors expressed in CHO cells. In conclusion, N-palmitoylethanolamide was, in our preparations, a weak ligand while its synthesized homologues or analogues were essentially inactive. Therefore, it seems unlikely that N-palmitoylethanolamide is an endogenous agonist of the CB2 receptors but it may be a compound with potential therapeutic applications since it may act via other mechanisms than cannabinoid CB1-CB2 receptor interactions. (C) 1999 Elsevier Science B.V. All rights reserved.