MEAD ETHANOLAMIDE, A NOVEL EICOSANOID, IS AN AGONIST FOR THE CENTRAL (CB1) AND PERIPHERAL (CB2) CANNABINOID RECEPTORS

The recently discovered endogenous agonist for the cannabinoid recepto r, anandamide (arachidonylethanolamide), can be formed enzymatically b y the condensation of arachidonic acid with ethanolamine. 5Z,8Z,11Z-Ei cosalrienoic acid (mead acid) has been found to substitute for arachid onic acid in the sn-2 position of phospholipids and accumulate during periods of dietary fatty acid deprivation in rats. In the present stud y, the chemically synthesized ethanolamide of mead acid was evaluated as a potential agonist at the two known subtypes of cannabinoid recept or: CB1 (central) and CB2 (peripheral). This compound was equipotent t o anandamide in competing with [H-3]CF55,940 binding to plasma membran es prepared from L cells expressing the human CB1 receptor and from AT t-20 cells expressing the human CB2 receptor. Mead ethanolamide was al so equipotent to anandamide in inhibiting forskolin-stimulated cAMP ac cumulation in cells expressing the CB1 receptor. It inhibited N-type c alcium currents with a lower potency than anandamide. Mead and arachid onic acid were equally efficacious as substrates for the enzymatic syn thesis of their respective ethanolamides in rat and adult human hippoc ampal P-2 membranes. Palmitic acid was not an effective substrate for the enzymatic synthesis of palmitoyl ethanolamide. Mead ethanolamide e xhibits several characteristics of a novel agonist to CB1 and CB2 rece ptors and may represent another candidate endogenous ligand for the CB 1 receptor. Due to the anticonvulsant properties of GABA and the posit ional similarity of L-serine to ethanolamine in membrane phospholipids , these compounds were synthetically coupled to arachidonic acid, and their resulting arachidonamides were tested as potential cannabinoid a gonists. The arachidonamides of GABA and L-serine were inactive in bot h binding and functional assays at the CB1 receptor.