The enzyme fatty acid amide hydrolase (FAAH) is widely expressed in brain and other tissues, and is capable of hydrolyzing arachidonyl ethanolamide (AEA) and other simple esters and amides with long unsaturated acyl chains. URB937 is a potent fatty acid amide hydrolase (FAAH) inhibitor (IC50 = 26.8 nM, in vitro) that does not penetrate the blood-brain barrier, thus preventing arachidonyl ethanolamide (AEA) deactivation only in peripheral tissues. Its ED50 value for FAAH inhibition in brain is 200-fold higher than the ED50 value for FAAH inhibition in liver when administered systemically in mice (40 mg/kg versus 0.2 mg/kg, respectively). Subcutaneous administration of URB937 reduces acetic acid-induced writhing in mice with an ED50 value of 0.1 mg/kg. A single 1 mg/kg injection of URB937 sufficiently attenuates behavioral responses elicited in mouse models of neuropathic and inflammatory pain. As a peripherally-specific FAAH inhibitor, URB937 may offer an alternative approach to pain therapy devoid of unwanted central effects.
