Analogues and homologues of N-palmitoylethanolamide, a putative endogenousCB2 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 a gonist of this receptor. We synthesized a series of 10 N-palmitoylethanolam ide homologues and analogues, varying by the elongation of the fatty acid c hain from caproyl to stearoyl and by the nature of the amide substituent, r espectively, and evaluated the affinity of these compounds to cannabinoid r eceptors 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 observ ed. [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 palmitoylethanolami de derivatives was observed in rat spleen slices. In RBL-2H3 cells, no bind ing 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 analogu es was measurable. These compounds do not recognize the human CB1 and CB2 r eceptors expressed in CHO cells. In conclusion, N-palmitoylethanolamide was , in our preparations, a weak ligand while its synthesized homologues or an alogues were essentially inactive. Therefore, it seems unlikely that N-palm itoylethanolamide 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 E lsevier Science B.V. All rights reserved.