Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide

1 The ability of a series of homologues and analogues of palmitoylethanolam ide to inhibit the uptake and fatty acid amidohydrolase (FAAH)-catalysed hy drolysis of [H-3]-anandamide ([H-3]-AEA) has been investigated. 2 Palmitoylethanolamide and homologues with chain lengths from 12 - 18 carb on atoms inhibited rat brain [H-3]-AEA metabolism with pI(50) values of sim ilar to5. Homologues with chain lengths less than or equal to eight carbon atoms gave <20% inhibition at 100 <mu>M. 3 R-palmitoyt-(2-methyl)ethanotamide. palmitoylisopropylamide and olcoyleth anolamide inhibited [H-3]-AEA metabolism with pI(50) values of 5.39 (compet itive inhibition), 4.89 (mixed type inhibition) and 5.33 (mixed type inhibi tion), respectively, 4 With the exception of oleoylethanolamide, the compounds did not produce d ramatic inhibition of [H-3]-WIN 55,212-2 binding to human CB2 receptors exp ressed on CHO cells. Palmitoylethanolamide, palmitoylisopropylamide and R-p almitoyl-(2-methyl)ethanolamide had modest effects upon [H-3]-CP 55,940 bin ding to human CB1 receptors expressed on CHO cells. 5 Most of the compounds had little effect upon the uptake of [H-3]-AEA into C6 and /or RBL-2H3 cells. However. palmitoylcyclohexamide (100 muM) and pa lmitoylisopropylamide (30 and 100 muM) produced more inhibition of [H-3]-AE A uptake than expected to result from inhibition of [HI-AEA metabolism alon e. 6 In intact C6 cells, palmitoylisopropylamide and oleoylethanolamide inhibi ted formation of [H-3]ethanolamine from [H-3]-AEA to a similar extent as AM 404, whereas palmitoylethanolamide, palmitoylcyclohexamide and R-palmitoyl- (2-methyl)ethanotamide were less effective. 7 These data provide useful information upon the ability of palmitoylethano lamide analogues to act as 'entourage' compounds. Palmitoylisopropylamide m ay prove useful as a template for design of compounds that reduce the cellu lar accumulation and metabolism of AEA without affecting either CB1 or CB2 receptors.