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Vol. 54, Issue 1, 180-188, July 1998
Department of Pharmacology and Toxicology, Medical College of
Wisconsin, Milwaukee, Wisconsin 53226 (W.S.E., C.J.H., C.S.K., W.B.C.),
and Departments of
Pharmacology and Biochemistry, The University of
Texas Southwestern Medical Center, Dallas, Texas 75235 (J.R.F.)
Arachidonylethanolamide (AEA), the putative endogenous ligand of
the cannabinoid receptor, has been shown to be a substrate for
lipoxygenase enzymes in vitro. One goal of this study
was to determine whether lipoxygenase-rich cells metabolize AEA.
[14C]AEA was converted by human polymorphonuclear
leukocytes (PMNs) to two major metabolites that comigrated with
synthetic 12(S)- and
15(S)-hydroxy-arachidonylethanolamide (HAEA). Human
platelets convert [14C]AEA to 12(S)-HAEA.
12(S)-HAEA binds to both CB1 and CB2 receptors with
approximately the same affinity as AEA. 12(R)-HAEA,
which is not produced by PMNs, has 2-fold lower affinity for the CB1 receptor and 10-fold lower affinity for the CB2 receptor than 12(S)-HAEA. 15-HAEA has a lower affinity than AEA for
both receptors, with Ki values of
738 and >1000 nM for CB1 and CB2 receptors, respectively. The addition of a hydroxyl group at C20 of AEA resulted in a ligand with the same affinity for the CB1 receptor but a 4-fold
lower affinity for the CB2 receptor than AEA. 12(S)-HAEA and 15-HAEA are poor substrates for AEA amidohydrolase and do not bind
to the AEA uptake carrier. In conclusion, the addition of a hydroxyl
group at C12 of the arachidonate backbone of AEA does not affect
binding to CB receptors but is likely to increase its half-life. The
addition of hydroxyl groups at other positions affects ligand affinity
for CB receptors; both the position of the hydroxyl group and the
configuration of the remaining double bonds are determinants of
affinity.
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