1: Br J Pharmacol  2002 Jun;136(3):452-8 

'Entourage' effects of N-acyl ethanolamines at human vanilloid receptors.
Comparison of effects upon anandamide-induced vanilloid receptor activation and
upon anandamide metabolism.

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

Neuroscience Research, Glaxo SmithKline Pharmaceuticals, New Frontiers Science
Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

1. The abilities of a series of saturated N-acyl ethanolamines and related
compounds to affect the ability of anandamide (AEA) to produce a Ca2+ influx
into human embryonic kidney cells expressing the human vanilloid receptor
(hVR1-HEK293 cells) has been investigated. 2. The C3:0, C4:0, C6:0 and C10:0
ethanolamides neither affected basal Ca2+-influx, nor the influx in response to
a submaximal concentration of AEA (1 microM). In contrast, the C12:0, C17:0,
C18:0 ethanolamides and the monounsaturated compound oleoylethanolamide (C18:1)
greatly potentiated the response to AEA. Palmitoylethanolamide (C16:0) produced
both a response per se and an augmentation of the response to AEA. 3.
Lauroylethanolamide (C12:0) produced a leftward shift in the dose-response curve
for AEA. EC50 values for AEA to produce Ca2+ influx into hVR1-HEK293 cells were
1.8, 1.5, 1.1 and 0.22 microM in the presence of 0, 1, 3 and 10 microM
lauroylethanolamide, respectively. Lauroylethanolamide did not affect the dose -
response curves to capsaicin. 4. Palmitoylethylamide was synthesized and found
to be a mixed-type inhibitor (K(i(slope)) 4.1 microM, K(i(intercept)) 66 microM)
of [3H]-AEA metabolism by rat brain membranes. 5. The -amide, -ethylamide,
-isopropylamide, -butylamide, -cyclohexamide and -trifluoromethyl ketone
analogues of palmitoylethanolamide had little or no effect on the Ca2+ influx
response to 1 microM AEA. 6. There was no obvious relation between the abilities
of the compounds to enhance the Ca2+ influx response to 1 microM AEA into
hVR1-HEK293 cells and to prevent the hydrolysis of AEA by rat brain membranes.
7. It is concluded that although palmitoylethanolamide has entourage-like
effects at VR1 receptors expressed on hVR1-HEK293 cells, other N-acyl
ethanolamines have even more dramatic potentiating effects. It is possible that
they may play an important role under conditions where their synthesis is
increased, such as in severe inflammation.

PMID: 12023948 [PubMed - indexed for MEDLINE]