O-689

(±)-2-Methyl arachidonoyl-2''-fluoroethylamide (2-Methyl-2''-fluoro AEA) is an analog of anandamide (AEA) in which the alcohol of the ethanolamide group has been removed and replaced with a fluorine atom. This substitution confers considerably increased binding affinity for the CB₁ receptor (K_i = 5.7 nM in rat brain). It also confers additional selectivity, in that binding to CB₂ is decreased relative to AEA. However, the in vivo activity of 2-fluoro AEA is enhanced much less than the binding affinity, because the analog remains a good substrate for FAAH and is rapidly hydrolyzed by this enzyme. 2-Methyl-2''-fluoro AEA is further modified by the addition of an α-methyl group at the C-2 position of arachidonic acid. This substitution confers enhanced metabolic stability. 2-Methyl-2''-fluoro AEA can fully substitute for Δ⁹-THC in animal self-administration tests, whereas AEA and 2-fluoro AEA cannot.

Met-F-AEA is a metabolically stable anandamine analogue. Met-F-AEA inhibits cell growth by activating apoptosis. Met-F-AEA has antitumor activity[1].

[1] Cozzolino R, et al. A metabolically stable analogue of anandamide, Met-F-AEA, inhibits human thyroid carcinoma cell lines by activation of apoptosis. Invest New Drugs. 2010 Apr;28(2):115-23. DOI:10.1007/s10637-009-9221-0