Uses
Fatty acid amide hydrolase (FAAH) degrades N-acyl ethanolamines (NAEs), including the endocannabinoid arachidonoyl ethanolamide (AEA). PF-3845 is a potent, selective, and irreversible inhibitor of FAAH (Ki = 0.23 μM). It covalently binds FAAH on Ser241 at the catalytic site, resulting in prolonged elevation of AEA in the brain and plasma in rats after treatment. PF-3845 significantly and persistently reduces inflammatory pain in rats through a cannabinoid receptor-dependent mechanism.[Cayman Chemical]
Biological Activity
pf-3845 is a highly potent and selective inhibitor of fatty acid amide hydrolase (faah) with ki value of 0.23μm [1].pf-3845 is a biaryl ether piperidine. it inhibits faah by a covalent, irreversible mechanism involving carbamylating faah's catalytic s241 nucleophile. it is found that, administration of pf-3845 to mice results a rapid and complete inactivation of faah in the brain. pf-3845 is highly selective for faah in vivo. it shows no activity to some other serine hydrolases as well as to a faah homologue, faah2. in addition, pf-3845-treated mice shows significant elevations in brain levels of aea, other naes and liver levels of aea, pea and oea. moreover, pf-3845 is found to inhibit pain responses in a rat model of inflammatory pain. it is also found to reverse lps-induced tactile allodynia in mice. this anti-allodynic effect requires activation of both cb1 and cb2 receptors which are the target receptors of the faah substrates [1, 2].
Biochem/physiol Actions
PF 3845 is a potent, irreversible inhibitor of fatty acid amide hydrolase (FAAH), the principle enzyme involved in the degradation of the endocannabinoid anandamide. The endocannabinoid system is a target for therapeutic pain relief. PF-3845 is a covalent inhibitor that carbamylates FAAH′s serine nucleophile. It high selectivity over other enzymes including FAAH-2. In mouse studies, PF-3845 has been shown to raise brain anandamide levels for up to 24 hr; and in a rat model it produced significant reduction of inflammatory pain..
References
[1] ahn k, johnson ds, mileni m, beidler d, long jz, mckinney mk, weerapana e, sadagopan n, liimatta m, smith se, lazerwith s, stiff c, kamtekar s, bhattacharya k, zhang y, swaney s, van becelaere k, stevens rc, cravatt bf. discovery and characterization of a highly selective faah inhibitor that reduces inflammatory pain. chem biol. 2009 apr 24;16(4):411-20.
[2] booker l, kinsey sg, abdullah ra, blankman jl, long jz, ezzili c, boger dl, cravatt bf, lichtman ah. the fatty acid amide hydrolase (faah) inhibitor pf-3845 acts in the nervous system to reverse lps-induced tactile allodynia in mice. br j pharmacol. 2012 apr;165(8):2485-96.
