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Titolo:
AN ENDOGENOUS SLEEP-INDUCING COMPOUND IS A NOVEL COMPETITIVE INHIBITOR OF FATTY-ACID AMIDE HYDROLASE
Autore:
PATRICELLI MP; PATTERSON JE; BOGER DL; CRAVATT BF;
Indirizzi:
SCRIPPS CLIN & RES INST,SKAGGS INST CHEM BIOL,10550 N TORREY PINES RDLA JOLLA CA 92037 SCRIPPS CLIN & RES INST,SKAGGS INST CHEM BIOL LA JOLLA CA 92037 SCRIPPS CLIN & RES INST,DEPT CHEM LA JOLLA CA 92037 SCRIPPS CLIN & RES INST,DEPT CELL BIOL LA JOLLA CA 92037
Titolo Testata:
Bioorganic & medicinal chemistry letters
fascicolo: 6, volume: 8, anno: 1998,
pagine: 613 - 618
SICI:
0960-894X(1998)8:6<613:AESCIA>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
ANANDAMIDE AMIDOHYDROLASE; BROMINE COMPOUND; BRAIN LIPIDS; RAT-BRAIN; HYDROLYSIS; CIS-9-OCTADECENAMIDE; RECEPTOR; OLEAMIDE; ENZYME;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
33
Recensione:
Indirizzi per estratti:
Citazione:
M.P. Patricelli et al., "AN ENDOGENOUS SLEEP-INDUCING COMPOUND IS A NOVEL COMPETITIVE INHIBITOR OF FATTY-ACID AMIDE HYDROLASE", Bioorganic & medicinal chemistry letters, 8(6), 1998, pp. 613-618

Abstract

7-Octyl gamma-bromoacetoacetate (O gamma Br), an endogenous compound originally isolated from human cerebrospinal fluid (CSF), has previously been demonstrated to increase REM sleep duration in cats. Based on the chemical structure of O gamma Br and its reported sleep-inducing effects, we synthesized O gamma Br along with chemically related analogs and tested these compounds as inhibitors of fatty acid amide hydrolase (FAAH), a brain enzyme that degrades neuromodulatory fatty acid amides. O gamma Br was found to competitively inhibit FAAH activity with IC50 and K-i values of 2.6 mu M and 0.8 mu M, respectively [for the (R)-enantiomer of O gamma Br (1)]. A set of synthetic analogs of O gammaBr was examined to define the structural features required for FAAH inhibition and inhibitor potencies were assessed at pH 9.0 (near the pHoptimum of FAAH) and pH 7.0. Interestingly, at pH 7.0 the gamma-halo beta-keto ester inhibitors proved to be significantly more potent thanthe trifluoromethyl ketone of oleic acid, one of the most potent FAAHinhibitors described to date. This study supports the possibility that O gamma Br may be a physiological regulator of FAAH activity and fatty acid amide levels in vivo. Additionally, the characterization of gamma-halo beta-keto esters as powerful FAAH inhibitors near physiological pH may aid in future studies of the enzymology and biological properties of FAAH. (C) 1998 Published by Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 03/04/20 alle ore 14:22:32