Animal models

Male C57BL/6 mice with TBI-induced deficits, CFA rat model with inflammatory pain

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Dosage form

Intraperitoneal injection, 30 min after TBI, and then once daily for 3 or 14 days; oral administration, 1–30 mg/kg;

Application

Treatment with PF3845 (5 mg/kg, i.p.) completely restored the ability of TBI mice to successfully alternate arms during maze exploration. PF3845 (5 mg/kg, 10 mg/kg, i.p.) significantly attenuated TBI-induced anxiogenic behavior. Treatment with PF3845 (5 mg/kg, 10 mg/kg, i.p.) significantly reduced TBI-induced deficits in fine motor movement. In a rat model of inflammatory pain, PF-3845 (1–30 mg/kg, oral administration) caused a dose-dependent inhibition of mechanical allodynia. In FAAH (-/-) mice and wild-type mice, treatment with PF-3845 (1–10 mg/kg i.p.) induced an anti-allodynic phenotype. PF-3845 (0.1–10 μg intraplantar) increased AEA levels in the brain and spinal cord. Intraplantar PF-3845 produced a partial reduction in allodynia.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

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].

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.