title: Synthesis and biological evaluation of new potential inhibitors of N-acylethanolamine hydrolyzing acid amidase.
abstract: N-Acylethanolamines, including N-palmitoyl-ethanolamine (PEA), are hydrolyzed to the corresponding fatty acids and ethanolamine by fatty acid amide hydrolase (FAAH). Recently, N-acylethanolamine-hydrolyzing acid amidase (NAAA) was identified as being able to specifically hydrolyze PEA. In order to find selective and effective inhibitors of this enzyme, we synthesized and screened several amides, retroamides, esters, retroesters and carbamates of palmitic acid (1-21) and esters with C15 and C17 alkyl chains (22-27). Cyclopentylhexadecanoate (13) exhibited the highest inhibitory activity on NAAA (IC(50)=10.0 microM), without inhibiting FAAH up to 50 microM. Compound 13 may become a useful template to design new NAAA inhibitors.
authors.affiliation: Department of Pharmaceutical Sciences, University of Salerno, Via Ponte don Melillo 84084, Fisciano, SA, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Saturnino
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrosino
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Chiara
authors.initials: C
authors.lastname: Palladino
authors.forename: Giovanni
authors.initials: G
authors.lastname: De Martino
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bisogno
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D004983:Ethanolamines; D006801:Humans; D006868:Hydrolysis; D010169:Palmitic Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D010169:Palmitic Acids; C005958:palmidrol; D000581:Amidohydrolases; C523108:NAAA protein, human