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Developing novel fatty acid amide hydrolase inhibitors for the treatment of pain
Author(s) -
Faloon Jordan,
Ezzili Cyrine,
Giuvelis Denise,
Lowery John J.,
McGlinchey Nicholas,
Boger Dale,
Bilsky Edward J.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.623.11
Fatty acid amide hydrolase (FAAH) is a regulator of several endogenous lipid amides including anandamide (AEA). Inhibition of FAAH elevates AEA levels to produce antiinflammatory and antinociceptive effects. OL‐135 is a well‐characterized reversible inhibitor of FAAH that produces broad‐spectrum antinociceptive effects in rodents. We have synthesized a series of next generation FAAH inhibitors to improve PK and PD properties of OL‐135. We report on the initial pharmacology of CE‐2‐313‐2, a α‐ketoheterocycle that has conformational restriction in the C2 acyl side chain of the parent OL‐135 structure. Intravenous administration produced dose‐related antinociception in the 52°C tail‐flick assay with a similar duration of action to that of morphine. At lower doses it also produced dose‐dependent reversal of thermal hyperalgesia and tactile allodynia in the carrageenan assay. In contrast, higher doses of CE‐2‐313‐2 did not produce full efficacy in this assay. One possible explanation is the reported activation of TRPV1 by higher concentrations of AEA following FAAH inhibition. Ongoing studies are investigating this possible mechanism and examining other aspects of CE‐2‐313‐2 pharmacology. This research was supported in part through an American Society of Pharmacology and Experimental Therapeutics SURF award.