• Yannick Fotio, Oscar Sasso, Roberto Ciccocioppo, and Daniele Piomelli.
• Departments of Anatomy and Neurobiology (Y.F., D.P.), Biological Chemistry (D.P.), and Pharmaceutical Sciences (D.P.), University of California, Irvine, California; Drug Discovery and Development, Istituto Italiano di Technologia, Genova, Italy (O.S.); and School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy (R.C.).
• J. Pharmacol. Exp. Ther. 2021 Aug 1; 378 (2): 70-76.

AbstractN-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase that stops the physiologic actions of palmitoylethanolamide, an endogenous lipid messenger that activates the transcription factor, peroxisome proliferator-activated receptor-α We have previously reported that the compound ARN19702 [(2-ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone] is an orally active, reversible NAAA inhibitor (IC50 on human NAAA = 230 nM) that produces remarkable protective effects against multiple sclerosis in mice. In the present study, we assessed the profile of ARN19702 in mouse and rat models of acute and neuropathic pain. Oral administration in male mice attenuated in a dose-dependent manner the spontaneous nocifensive response elicited by intraplantar formalin injection and the hypersensitivity caused by intraplantar carrageenan injection, paw incision, or sciatic nerve ligation. In male rats, ARN19702 reduced nociception associated with paclitaxel-induced neuropathy without development of subacute antinociceptive tolerance. Finally, ARN19702 (30 mg/kg, oral) did not produce place preference or alter exploratory motor behavior in male mice. The findings support the conclusion that NAAA is a suitable molecular target for the discovery of efficacious analgesic drugs devoid of rewarding potential. SIGNIFICANCE STATEMENT: This study evaluated the pharmacological profile of the orally bioavailable N-acylethanolamine acid amidase (NAAA) inhibitor (2-ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone (ARN19702) in mouse and rat models of neurogenic and inflammatory pain. The compound's potential rewarding and sedative effects were also examined. It is concluded that ARN19702 exhibits a broad analgesic profile that can be generalized across rodent species. The findings point to NAAA as a control node in the processing of neuropathic and inflammatory pain and to ARN19702 as a lead to uncover novel pain therapeutics devoid of addictive potential .Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.

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