Synthesis and biological evaluation of new potential inhibitors of N-acylethanolamine hydrolyzing acid amidase

被引：43

作者：

Saturnino, Carmela ^{[2
]}

Petrosino, Stefania ^{[1
,2
]}

Ligresti, Alessia ^{[1
]}

Palladino, Chiara ^{[2
]}

De Martino, Giovanni ^{[2
]}

Bisogno, Tiziana ^{[1
]}

Di Marzo, Vincenzo ^{[1
]}

机构：

[1] CNR, Inst Biomol Chem, Endocannabinoid Res Grp, I-80078 Pozzuoli, NA, Italy

[2] Univ Salerno, Dept Pharmaceut Sci, I-84084 Fisciano, SA, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 03期

关键词：

N-Acylethanolamines; Palmitoylethanolamide; Inflammation; Degradation; Enzyme; Endocannabinoid; Vanilloid; NAAA; MOLECULAR CHARACTERIZATION; ACUTE-INFLAMMATION; PALMITOYLETHANOLAMIDE; ANANDAMIDE; HYDROLASE; RECEPTOR; PAIN; BIOSYNTHESIS; INVOLVEMENT; ESTERS;

D O I：

10.1016/j.bmcl.2009.11.134

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 (IC50 = 10.0 mu M), without inhibiting FAAH up to 50 mu M. Compound 13 may become a useful template to design new NAAA inhibitors. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：1210 / 1213

页数：4

共 27 条

[21] The orphan receptor GPR55 is a novel cannabinoid receptor
Ryberg, E.
Larsson, N.
Sjoegren, S.
Hjorth, S.
Hermansson, N-O
Leonova, J.
Elebring, T.
Nilsson, K.
Drmota, T.
Geasley, P. J.
[J]. BRITISH JOURNAL OF PHARMACOLOGY, 2007, 152 (07) : 1092 - 1101
[22] 'Entourage' effects of N-acyl ethanolamines at human vanilloid receptors.: Comparison of effects upon anandamide-induced vanilloid receptor activation and upon anandamide metabolism
Smart, D
Jonsson, KO
Vandevoorde, S
Lambert, DM
Fowler, CJ
[J]. BRITISH JOURNAL OF PHARMACOLOGY, 2002, 136 (03) : 452 - 458
[23] Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase
Tsuboi, K
Sun, YX
Okamoto, Y
Araki, N
Tonai, T
Ueda, N
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (12) : 11082 - 11092
[24] N-cyclohexanecarbonylpentadecylamine:: a selective inhibitor of the acid amidase hydrolysing N-acylethanolamines, as a tool to distinguish acid amidase from fatty acid amide hydrolase
Tsuboi, K
Hilligsmann, C
Vandevoorde, S
Lambert, DM
Ueda, N
[J]. BIOCHEMICAL JOURNAL, 2004, 379 : 99 - 106
[25] A second N-acylethanolamine hydrolase in mammalian tissues
Ueda, N
Tsuboi, K
Lambert, DM
[J]. NEUROPHARMACOLOGY, 2005, 48 (08) : 1079 - 1085
[26] Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance
Ueda, N
Yamanaka, K
Yamamoto, S
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (38) : 35552 - 35557
[27] Esters, retroesters, and a retroamide of palmitic acid:: Pool for the first selective inhibitors of N-palmitoylethanolamine selective acid amidase
Vandevoorde, S
Tsuboi, K
Ueda, N
Jonsson, KO
Fowler, CJ
Lambert, DM
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (21) : 4373 - 4376

← 1 2 3 →