Human Platelets and Polymorphonuclear Leukocytes Synthesize Oxygenated Derivatives of Arachidonylethanolamide (Anandamide): Their Affinities for Cannabinoid Receptors and Pathways of Inactivation
- 1 July 1998
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 54 (1), 180-188
- https://doi.org/10.1124/mol.54.1.180
Abstract
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.Keywords
This publication has 31 references indexed in Scilit:
- Potentiation of anandamide hypotension by the transport inhibitor, AM404European Journal of Pharmacology, 1997
- The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein couplingFEBS Letters, 1995
- Cannabinoid ligand-receptor signaling in the mouse uterus.Proceedings of the National Academy of Sciences, 1995
- Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide.Proceedings of the National Academy of Sciences, 1995
- Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid ReceptorScience, 1992
- Enhancement of the antiaggregatory activity of prostacyclin by propranolol in human platelets.Circulation, 1985
- Arachidonic acid metabolism in polymorphonuclear leukocytesProceedings of the National Academy of Sciences, 1979
- Synthesis from arachidonic acid of potential prostaglandin precursorsJournal of the Chemical Society, Perkin Transactions 1, 1979
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976
- Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reactionBiochemical Pharmacology, 1973