Potential analgesic effects of a novel N-acylethanolamine acid amidase inhibitor F96 through PPAR-α.

Abstract

Pharmacological blockade of N-acylethanolamine acid amidase (NAAA) activity is an available approach for inflammation and pain control through restoring the ability of endogenous PEA. But the recently reported NAAA inhibitors suffer from the chemical and biological unstable properties, which restrict functions of NAAA inhibition in vivo. It is still unrevealed whether systematic inhibition of NAAA could modulate PEA-mediated pain signalings. Here we reported an oxazolidinone imide compound 3-(6-phenylhexanoyl) oxazolidin-2-one (F96), which potently and selectively inhibited NAAA activity (IC50 = 270 nM). Intraperitoneal (i.p.) injection of F96 (3-30 mg/kg) dose-dependently reduced ear edema and restored PEA levels of ear tissues in 12-O-Tetradecanoylphorbol-13-acetate (TPA) induced ear edema models. Furthermore, F96 inhibited acetic acid-induced writhing and increased spared nerve injury induced tactile allodynia thresholds in a dose-dependent manner. Pharmacological effects of F96 (10 mg/kg, i.p.) on various animal models were abolished in PPAR-α(-/-) mice, and were prevented by PPAR-α antagonist MK886 but not by canabinoid receptor type 1 (CB1) antagonist Rimonabant nor canabinoid receptor type 2 (CB2) antagonist SR144528. Zebrafish embryos experiments showed better security and lower toxicity for F96 than ibuprofen. These results revealed that F96 might be useful in treating inflammatory and neuropathic pain by NAAA inhibition depending on PPAR-α receptors.

• Authors: Longhe Yang, Long Li, Ling Chen, Yanting Li, Huixia Chen, Yuhang Li, Guangnian Ji, Donghai Lin, Zuguo Liu, Yan Qiu
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 13565 (Aug 27 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26310614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(6-phenylhexanoyl)oxazolidin-2-one
• Analgesics
• Enzyme Inhibitors
• Ethanolamines
• Fatty Acids
• N-acylethanolamines
• Oxazolidinones
• PPAR alpha
• Amidohydrolases
• amidase
• Acetic Acid

Topics

• Acetic Acid
• Amidohydrolases (antagonists & inhibitors, metabolism)
• Analgesics (chemistry, pharmacology, therapeutic use)
• Animals
• Disease Models, Animal
• Ear (pathology)
• Edema (complications, drug therapy)
• Enzyme Inhibitors (chemistry, pharmacology)
• Ethanolamines (metabolism)
• Fatty Acids (metabolism)
• HEK293 Cells
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Neuralgia (drug therapy, etiology)
• Oxazolidinones (chemistry, pharmacology, therapeutic use)
• PPAR alpha (metabolism)
• RAW 264.7 Cells
• Sciatic Nerve (injuries, pathology)
• Zebrafish