TI: Effects of homologues and analogues of palmitoylethanolamide
upon the inactivation of the endocannabinoid anandamide.
AU: Jonsson,-K-O; Vandevoorde,-S; Lambert,-D-M; Tiger,-G; Fowler,-C-J
AD: Department of Pharmacology and Clinical Neuroscience, Umea
University, SE-901 87 Umea, Sweden. Kentolov.Jonsson@pharm.umu.se
SO: Br-J-Pharmacol. 2001 Aug; 133(8): 1263-75
JN: British-journal-of-pharmacology
PY: 2001
AB: 1. The ability of a series of homologues and analogues of
palmitoylethanolamide to inhibit the uptake and fatty acid amidohydrolase
(FAAH)-catalysed hydrolysis of [(3)H]-anandamide ([(3)H]-AEA) has been
investigated. 2. Palmitoylethanolamide and homologues with chain lengths
from 12 - 18 carbon atoms inhibited rat brain [(3)H]-AEA metabolism with
pI(50) values of approximately 5. Homologues with chain lengths < or
= eight carbon atoms gave < 20% inhibition at 100 microM. 3. R-palmitoyl-(2-methyl)ethanolamide,
palmitoylisopropylamide and oleoylethanolamide inhibited [(3)H]-AEA metabolism
with pI(50) values of 5.39 (competitive inhibition), 4.89 (mixed type inhibition)
and 5.33 (mixed type inhibition), respectively. 4. With the exception of
oleoylethanolamide, the compounds did not produce dramatic inhibition of
[(3)H]-WIN 55,212-2 binding to human CB(2) receptors expressed on CHO cells.
Palmitoylethanolamide, palmitoylisopropylamide and R-palmitoyl-(2-methyl)ethanolamide
had modest effects upon [(3)H]-CP 55,940 binding to human CB(1) receptors
expressed on CHO cells. 5. Most of the compounds had little effect upon
the uptake of [(3)H]-AEA into C6 and/or RBL-2H3 cells. However, palmitoylcyclohexamide
(100 microM) and palmitoylisopropylamide (30 and 100 microM) produced more
inhibition of [(3)H]-AEA uptake than expected to result from inhibition
of [(3)H]-AEA metabolism alone. 6. In intact C6 cells, palmitoylisopropylamide
and oleoylethanolamide inhibited formation of [(3)H]-ethanolamine from
[(3)H]-AEA to a similar extent as AM404, whereas palmitoylethanolamide,
palmitoylcyclohexamide and R-palmitoyl-(2-methyl)ethanolamide were less
effective. 7. These data provide useful information upon the ability of
palmitoylethanolamide analogues to act as 'entourage' compounds. Palmitoylisopropylamide
may prove useful as a template for design of compounds that reduce the
cellular accumulation and metabolism of AEA without affecting either CB(1)
or CB(2) receptors.