1: J Med Chem  2003 Apr 10;46(8):1440-8 

Modifications of the ethanolamine head in N-palmitoylethanolamine: synthesis and
evaluation of new agents interfering with the metabolism of anandamide.

Vandevoorde S, Jonsson KO, Fowler CJ, Lambert DM.

Unite de Chimie Pharmaceutique et de Radiopharmacie, Universite Catholique de
Louvain, Avenue Mounier, 73, UCL-CMFA 73.40, B-1200 Brussels, Belgium.

The endogenous fatty acid amide anandamide (AEA) has, as a result of its actions
on cannabinoid and vanilloid receptors, a number of important pharmacological
properties including effects on nociception, memory processes, spasticity, and
cell proliferation. Inhibition of the metabolism of AEA, catalyzed by fatty acid
amide hydrolase (FAAH), potentiates the actions of AEA in vivo and therefore may
be a useful target for drug development. In the present study, we have
investigated whether substitution of the headgroup of the endogenous alternative
FAAH substrate palmitoylethanolamide (PEA) can result in the identification of
novel compounds preventing AEA metabolism. Thirty-seven derivatives of PEA were
synthesized, with the C16 long chain of palmitic acid kept intact, and
comprising 20 alkylated, 12 aromatic, and 4 halogenated amides. The ability of
the PEA derivatives to inhibit FAAH-catalyzed hydrolysis of [(3)H]AEA was
investigated using rat brain homogenates as a source of FAAH. Inhibition curves
were analyzed to determine the potency of the inhibitable fraction (pI(50)
values) and the maximal attained inhibition for the compound, given that
solubility in an aqueous environment is a major issue for these compounds. In
the alkylamide family, palmitoylethylamide and palmitoylallylamide were
inhibitors of AEA metabolism with pI(50) values of 5.45 and 5.47, respectively.
Halogenated derivatives (Cl and Br) exhibit pI(50) values of approximately 5.5
but rather low percentages of maximal inhibition. The -OH group of the ethyl
head chain of N-palmitoylethanolamine was not necessary for interaction with
FAAH. Amides containing aromatic moieties were less potent inhibitors of AEA
metabolism. Compounds containing amide and ester bonds, 13 and 37, showed pI(50)
values of 4.99 and 5.08, respectively. None of the compounds showed obvious
affinity for CB(1) or CB(2) receptors expressed on Chinese hamster ovary (CHO)
cells. It is concluded that although none of the compounds were dramatically
more potent than PEA itself at reducing the metabolism of AEA, the lack of
effect of the compounds at CB(1) and CB(2) receptors makes them useful templates
for development of possible therapeutic FAAH inhibitors.

PMID: 12672243 [PubMed - indexed for MEDLINE]