2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor

doi:10.1073/pnas.061029898

2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB₁ receptor

^*Department of Medicinal Chemistry and Natural Products, Hebrew University Medical Faculty, Jerusalem 91120, Israel; ^†Chemistry and Chemical Technology Department, Faculty of Science and Technology, P.O. Box 20002, Al-Quds University, Abu-Deis, West Bank, Palestinian Authority; ^‡Department of Behavioral Sciences, College of Judea and Samaria, Ariel 88437, Israel; ^§Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel; and ^¶Department of Biological Chemistry and The Wolfson Centre for Applied Structural Biology, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel

Communicated by L. L. Iversen, University of Oxford, Oxford, United Kingdom (received for review November 23, 2000)

Abstract

Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids—arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series—and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB₁ cannabinoid receptor (K _i = 21.2 ± 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB₂ receptor (K _i > 3 μM).

Footnotes

↵ ‖ To whom reprint requests should be addressed at: Hebrew University, Department of Medicinal Chemistry and Natural Products, Faculty of Medicine, Ein Kerem Campus, Jerusalem 91120, Israel. E-mail: Mechou{at}cc.huji.ac.il.
Abbreviations:

2-AG,

2-arachidonoyl glycerol;

2D,

two-dimensional