期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 36, 期 1, 页码 940-953出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2021.1875459
关键词
Flurbiprofen amides; FAAH inhibition; fatty acid amide hydrolase; endocannabinoid; cyclooxygenase; non-steroidal anti-inflammatory drugs; hyperalgesia; allodynia
资金
- University of Cagliari [FIR 2018-19]
- fellowship of Regione Campania [B61C17000070007 -SATIN]
- NVIDIA Corporation
The study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models.
Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a K-i value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NF kappa B in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds.
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