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). We have reported the isolation and identification of two types of endogenous cannabinoids that bind and activate the known cannabinoid receptors CB1 and CB2. Arachidonoyl ethanolamide (anandamide; ref. 1) and later two more polyunsaturated fatty acid ethanol amides (2) were found in porcine brain. An ester, 2-arachidonoyl glycerol (2-AG) was isolated by us from canine gut (3) and by Sugiura et al. from brain (4). Anandamide and 2-AG have been the objects of numerous investigations in various areas of biology and have been found to affect processes in the nervous, cardiovascular, immune, and reproductive systems (5–8). They interact with many neurotransmitters and affect hormone levels (9–10). This ubiquity of effects led us to look for additional endocannabinoids. We report now that we have isolated from porcine brain a third endocannabinoid, 2-arachidonyl glyceryl ether, which we have named noladin ether (Fig. 1).
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