2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB ₁ receptor

TLDR

Two types of endogenous cannabinoid‑receptor agonists have been identified: the ethanolamide anandamide and the ester 2‑arachidonoyl glycerol. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and confirmed by comparison with a synthetic sample. We report a third ether‑type endocannabinoid, 2‑arachidonyl glyceryl ether (noladin ether), isolated from porcine brain, which binds to the CB1 receptor (Ki = 21.2 ± 0.5 nM) and induces sedation, hypothermia, intestinal immobility, and mild antinociception in mice, while binding weakly to CB2 (Ki > 3 µM).

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 CB 1 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 CB 2 receptor ( K i > 3 μM).