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

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 microM).

Figure 1

Synthesis of noladin ether: step a, LiAlH₄/ether, 25°C; step b, CH₃SO₂Cl/pyridine, 25°C; step c, benzylideneglycerol-KOH/benzene, 25°C; step d, HCl/CH₃OH, 25°C. Percentages indicate yields of reactions.

Figure 2

Competitive inhibition of [³H]HU-243 binding by natural noladin ether. For details see Materials and Methods.

Figure 3

Overlay of HPLC chromatograms of natural and synthetic noladin ether. For details see Materials and Methods.

Figure 4

Electron impact/mass spectrum of di(trimethylsilyl) derivative of natural noladin ether. The relative intensity of the peaks above 275 m/z is given (Inset). For details see Materials and Methods.

Figure 5

Performance of mice injected with synthetic noladin ether on pharmacological tests for cannabinoid effects. Noladin ether was injected 10 min before the start of testing. *, P < 0.05; **, P < 0.01 (difference from vehicle controls). For further details see Materials and Methods.