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Pesquisa : D08.811.277.352.100.500 [Categoria DeCS]
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[PMID]:28936880
[Au] Autor:Granchi C; Caligiuri I; Bertelli E; Poli G; Rizzolio F; Macchia M; Martinelli A; Minutolo F; Tuccinardi T
[Ad] Endereço:a Department of Pharmacy , University of Pisa , Pisa , Italy.
[Ti] Título:Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitors.
[So] Source:J Enzyme Inhib Med Chem;32(1):1240-1252, 2017 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Monoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol. A wide number of MAGL inhibitors are reported in literature; however, many of them are characterised by an irreversible mechanism of action and this behavior determines an unwanted chronic MAGL inactivation, which acquires a functional antagonism of the endocannabinoid system. The possible use of reversible MAGL inhibitors has only recently been explored, due to the lack of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of terphenyl-2-methyloxazol-5(4H)-one derivatives characterised by a reversible MAGL-inhibition mechanism. Among them, compound 20b showed to be a potent MAGL reversible inhibitor (IC = 348 nM) with a good MAGL/FAAH selectivity. Furthermore, this compound showed antiproliferative activities against two different cancer cell lines that overexpress MAGL.
[Mh] Termos MeSH primário: Monoacilglicerol Lipases/antagonistas & inibidores
Oxazóis/farmacologia
Compostos de Terfenil/farmacologia
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Monoacilglicerol Lipases/metabolismo
Oxazóis/síntese química
Oxazóis/química
Proteínas Recombinantes/metabolismo
Relação Estrutura-Atividade
Compostos de Terfenil/síntese química
Compostos de Terfenil/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-((4,4'-dimethoxy-(1,1':4',1'-terphenyl)-2'-yl)methylene)-2-methyloxazol-5(4H)-one); 0 (Oxazoles); 0 (Recombinant Proteins); 0 (Terphenyl Compounds); EC 3.1.1.23 (Monoacylglycerol Lipases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1375484


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[PMID]:28768662
[Au] Autor:Ahmad A; Daneva Z; Li G; Dempsey SK; Li N; Poklis JL; Lichtman A; Li PL; Ritter JK
[Ad] Endereço:Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia.
[Ti] Título:Stimulation of diuresis and natriuresis by renomedullary infusion of a dual inhibitor of fatty acid amide hydrolase and monoacylglycerol lipase.
[So] Source:Am J Physiol Renal Physiol;313(5):F1068-F1076, 2017 Nov 01.
[Is] ISSN:1522-1466
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The renal medulla, considered critical for the regulation of salt and water balance and long-term blood pressure control, is enriched in anandamide and two of its major metabolizing enzymes, cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH). Infusion of anandamide (15, 30, and 60 nmol·min ·kg ) into the renal medulla of C57BL/6J mice stimulated diuresis and salt excretion in a COX-2- but not COX-1-dependent manner. To determine whether endogenous endocannabinoids in the renal medulla can elicit similar effects, the effects of intramedullary isopropyl dodecyl fluorophosphate (IDFP), which inhibits the two major endocannabinoid hydrolases, were studied. IDFP treatment increased the urine formation rate and sodium excretion in a COX-2- but not COX-1-dependent manner. Neither anandamide nor IDFP affected the glomerular filtration rate. Neither systemic (0.625 mg·kg ·30 min iv) nor intramedullary (15 nmol·min ·kg ·30 min ) IDFP pretreatment before intramedullary anandamide (15-30 nmol·min ·kg ) strictly blocked effects of anandamide, suggesting that hydrolysis of anandamide was not necessary for its diuretic effect. Intramedullary IDFP had no effect on renal blood flow but stimulated renal medullary blood flow. The effects of IDFP on urine flow rate and medullary blood flow were FAAH-dependent as demonstrated using FAAH knockout mice. Analysis of mouse urinary PGE concentrations by HPLC-electrospray ionization tandem mass spectrometry showed that IDFP treatment decreased urinary PGE These data are consistent with a role of FAAH and endogenous anandamide acting through a COX-2-dependent metabolite to regulate diuresis and salt excretion in the mouse kidney.
[Mh] Termos MeSH primário: Amidoidrolases/antagonistas & inibidores
Diurese
Inibidores Enzimáticos/farmacologia
Monoacilglicerol Lipases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Amidoidrolases/metabolismo
Animais
Ácidos Araquidônicos/metabolismo
Ciclo-Oxigenase 2/metabolismo
Diurese/efeitos dos fármacos
Endocanabinoides/metabolismo
Medula Renal/efeitos dos fármacos
Medula Renal/metabolismo
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Monoacilglicerol Lipases/metabolismo
Natriurese/efeitos dos fármacos
Natriurese/fisiologia
Alcamidas Poli-Insaturadas/metabolismo
Circulação Renal/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arachidonic Acids); 0 (Endocannabinoids); 0 (Enzyme Inhibitors); 0 (Polyunsaturated Alkamides); EC 1.14.99.- (Ptgs2 protein, mouse); EC 1.14.99.1 (Cyclooxygenase 2); EC 3.1.1.23 (Monoacylglycerol Lipases); EC 3.5.- (Amidohydrolases); EC 3.5.1.- (fatty-acid amide hydrolase); UR5G69TJKH (anandamide)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171114
[Lr] Data última revisão:
171114
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1152/ajprenal.00196.2017


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[PMID]:28486208
[Au] Autor:Ahamed M; Attili B; van Veghel D; Ooms M; Berben P; Celen S; Koole M; Declercq L; Savinainen JR; Laitinen JT; Verbruggen A; Bormans G
[Ad] Endereço:Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, Campus Gasthuisberg O&N2, Herestraat 49 Box 821, BE-3000 Leuven, Belgium.
[Ti] Título:Synthesis and preclinical evaluation of [ C]MA-PB-1 for in vivo imaging of brain monoacylglycerol lipase (MAGL).
[So] Source:Eur J Med Chem;136:104-113, 2017 Aug 18.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:MAGL is a potential therapeutic target for oncological and psychiatric diseases. Our objective was to develop a PET tracer for in vivo quantification of MAGL. We report [ C]MA-PB-1 as an irreversible MAGL inhibitor PET tracer. The in vitro inhibitory activity, ex vivo distribution, brain kinetics and specificity of [ C]MA-PB-1 binding were studied. Ex vivo biodistribution and microPET showed good brain uptake which could be blocked by pretreatment with both MA-PB-1 and a structurally non-related MAGL inhibitor MJN110. These initial results suggest that [ C]MA-PB-1 is a suitable tracer for in vivo imaging of MAGL.
[Mh] Termos MeSH primário: Compostos de Benzil/farmacologia
Encéfalo/enzimologia
Inibidores Enzimáticos/farmacologia
Monoacilglicerol Lipases/antagonistas & inibidores
Piperazinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Compostos de Benzil/síntese química
Compostos de Benzil/química
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Feminino
Macaca mulatta
Camundongos
Estrutura Molecular
Monoacilglicerol Lipases/metabolismo
Piperazinas/síntese química
Piperazinas/química
Tomografia por Emissão de Pósitrons
Traçadores Radioativos
Ratos
Ratos Wistar
Relação Estrutura-Atividade
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (((11)C)MA-PB-1); 0 (Benzyl Compounds); 0 (Enzyme Inhibitors); 0 (Piperazines); 0 (Radioactive Tracers); EC 3.1.1.23 (Monoacylglycerol Lipases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170510
[St] Status:MEDLINE


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[PMID]:28404744
[Au] Autor:Karwad MA; Couch DG; Theophilidou E; Sarmad S; Barrett DA; Larvin M; Wright KL; Lund JN; O'Sullivan SE
[Ad] Endereço:School of Medicine, Royal Derby Hospital, University of Nottingham, Nottingham, United Kingdom.
[Ti] Título:The role of CB in intestinal permeability and inflammation.
[So] Source:FASEB J;31(8):3267-3277, 2017 Aug.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The endocannabinoid system has previously been shown to play a role in the permeability and inflammatory response of the human gut. The goal of our study was to determine the effects of endogenous anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) on the permeability and inflammatory response of intestinal epithelium under normal, inflammatory, and hypoxic conditions. Human intestinal mucosa was modeled using Caco-2 cells. Human tissue was collected from planned colorectal resections. Accumulation of AEA and 2-AG was achieved by inhibiting their metabolizing enzymes URB597 (a fatty acid amide hydrolase inhibitor) and JZL184 (a monoacylglycerol lipase inhibitor). Inflammation and ischemia were simulated with TNF-α and IFN-γ and oxygen deprivation. Permeability changes were measured by transepithelial electrical resistance. The role of the CB receptor was explored using CB -knockdown (CB Kd) intestinal epithelial cells. Endocannabinoid levels were measured using liquid chromatography-mass spectrometry. Cytokine secretion was measured using multiplex and ELISA. URB597 and JZL184 caused a concentration-dependent increase in permeability CB ( < 0.0001) and decreased cytokine production. Basolateral application of JZL184 decreased permeability CB ( < 0.0001). URB597 and JZL184 increased the enhanced (worsened) permeability caused by inflammation and hypoxia ( < 0.0001 and < 0.05). CB Kd cells showed reduced permeability response to inflammation ( < 0.01) but not hypoxia. 2-AG levels were increased in response to inflammation and hypoxia in Caco-2 cells. In human mucosal tissue, inflammation increased the secretion of granulocyte macrophage-colony stimulating factor, IL-12, -13, and -15, which was prevented with treatment with URB597 and JZL184, and was inhibited by a CB antagonist. The results of this study show that endogenous AEA and 2-AG production and CB activation play a key modulatory roles in normal intestinal mucosa permeability and in inflammatory and hypoxic conditions.-Karwad, M. A., Couch, D. G., Theophilidou, E., Sarmad, S., Barrett, D. A., Larvin, M., Wright, K. L., Lund, J. N., O'Sullivan, S. E. The role of CB in intestinal permeability and inflammation.
[Mh] Termos MeSH primário: Ácidos Araquidônicos/metabolismo
Endocanabinoides/metabolismo
Glicerídeos/metabolismo
Intestinos/fisiologia
Alcamidas Poli-Insaturadas/metabolismo
Receptor CB1 de Canabinoide/metabolismo
[Mh] Termos MeSH secundário: Amidoidrolases/genética
Amidoidrolases/metabolismo
Benzamidas/farmacologia
Benzodioxóis/farmacologia
Células CACO-2
Carbamatos/farmacologia
Neoplasias Colorretais/metabolismo
Citocinas/genética
Citocinas/metabolismo
Impedância Elétrica
Regulação da Expressão Gênica/efeitos dos fármacos
Regulação da Expressão Gênica/fisiologia
Seres Humanos
Inflamação/metabolismo
Mucosa Intestinal/metabolismo
Mucosa Intestinal/patologia
Intestinos/metabolismo
Intestinos/patologia
Monoacilglicerol Lipases/antagonistas & inibidores
Monoacilglicerol Lipases/metabolismo
Consumo de Oxigênio
Permeabilidade
Piperidinas/farmacologia
Receptor CB1 de Canabinoide/genética
Técnicas de Cultura de Tecidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arachidonic Acids); 0 (Benzamides); 0 (Benzodioxoles); 0 (Carbamates); 0 (Cytokines); 0 (Endocannabinoids); 0 (Glycerides); 0 (JZL 184); 0 (Piperidines); 0 (Polyunsaturated Alkamides); 0 (Receptor, Cannabinoid, CB1); 0 (cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester); 8D239QDW64 (glyceryl 2-arachidonate); EC 3.1.1.23 (Monoacylglycerol Lipases); EC 3.5.- (Amidohydrolases); EC 3.5.1.- (fatty-acid amide hydrolase); UR5G69TJKH (anandamide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601346R


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[PMID]:28247204
[Au] Autor:Smaga I; Jastrzebska J; Zaniewska M; Bystrowska B; Gawlinski D; Faron-Górecka A; Broniowska Z; Miszkiel J; Filip M
[Ad] Endereço:Department of Toxicology, Faculty of Pharmacy, College of Medicum, Jagiellonian University, Medyczna 9, PL 30-688, Kraków, Poland.
[Ti] Título:Changes in the Brain Endocannabinoid System in Rat Models of Depression.
[So] Source:Neurotox Res;31(3):421-435, 2017 Apr.
[Is] ISSN:1476-3524
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A growing body of evidence implicates the endocannabinoid (eCB) system in the pathophysiology of depression. The aim of this study was to investigate the influence of changes in the eCB system, such as levels of neuromodulators, eCB synthesizing and degrading enzymes, and cannabinoid (CB) receptors, in different brain structures in animal models of depression using behavioral and biochemical analyses. Both models used, i.e., bulbectomized (OBX) and Wistar Kyoto (WKY) rats, were characterized at the behavioral level by increased immobility time. In the OBX rats, anandamide (AEA) levels were decreased in the prefrontal cortex, hippocampus, and striatum and increased in the nucleus accumbens, while 2-arachidonoylglycerol (2-AG) levels were increased in the prefrontal cortex and decreased in the nucleus accumbens with parallel changes in the expression of eCB metabolizing enzymes in several structures. It was also observed that CB receptor expression decreased in the hippocampus, dorsal striatum, and nucleus accumbens, and CB receptor expression decreased in the prefrontal cortex and hippocampus. In WKY rats, the levels of eCBs were reduced in the prefrontal cortex (2-AG) and dorsal striatum (AEA) and increased in the prefrontal cortex (AEA) with different changes in the expression of eCB metabolizing enzymes, while the CB receptor density was increased in several brain regions. These findings suggest that dysregulation in the eCB system is implicated in the pathogenesis of depression, although neurochemical changes were linked to the particular brain structure and the factor inducing depression (surgical removal of the olfactory bulbs vs. genetic modulation).
[Mh] Termos MeSH primário: Ácidos Araquidônicos/metabolismo
Encéfalo/metabolismo
Depressão/metabolismo
Endocanabinoides/metabolismo
Glicerídeos/metabolismo
Alcamidas Poli-Insaturadas/metabolismo
Receptor CB1 de Canabinoide/biossíntese
Receptor CB2 de Canabinoide/biossíntese
[Mh] Termos MeSH secundário: Amidoidrolases/biossíntese
Animais
Modelos Animais de Doenças
Resposta de Imobilidade Tônica
Lipase Lipoproteica/biossíntese
Masculino
Monoacilglicerol Lipases/biossíntese
Bulbo Olfatório/cirurgia
Fosfolipase D/biossíntese
Ratos
Ratos Endogâmicos WKY
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arachidonic Acids); 0 (Endocannabinoids); 0 (Glycerides); 0 (Polyunsaturated Alkamides); 0 (Receptor, Cannabinoid, CB1); 0 (Receptor, Cannabinoid, CB2); 8D239QDW64 (glyceryl 2-arachidonate); EC 3.1.1.23 (Monoacylglycerol Lipases); EC 3.1.1.34 (Lipoprotein Lipase); EC 3.1.4.4 (NAPE-PLD protein, rat); EC 3.1.4.4 (Phospholipase D); EC 3.5.- (Amidohydrolases); EC 3.5.1.- (fatty-acid amide hydrolase); UR5G69TJKH (anandamide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170302
[St] Status:MEDLINE
[do] DOI:10.1007/s12640-017-9708-y


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[PMID]:28193521
[Au] Autor:Pagano E; Borrelli F; Orlando P; Romano B; Monti M; Morbidelli L; Aviello G; Imperatore R; Capasso R; Piscitelli F; Buono L; Di Marzo V; Izzo AA
[Ad] Endereço:Department of Pharmacy, University of Naples Federico II, Naples, Italy.
[Ti] Título:Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis.
[So] Source:Pharmacol Res;119:227-236, 2017 May.
[Is] ISSN:1096-1186
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Colorectal cancer (CRC) is a major health problem in Western countries. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) exerts antiproliferative actions in a number of tumoral cell lines, including CRC cells. Monoacylglycerol lipase (MAGL), a serine hydrolase that inactivates 2-AG, is highly expressed in aggressive human cancer cells. Here, we investigated the role of MAGL in experimental colon carcinogenesis. The role of MAGL was assessed in vivo by using the xenograft and the azoxymethane models of colon carcinogenesis; MAGL expression was evaluated by RT-PCR and immunohistochemistry; 2-AG levels were measured by liquid chromatography mass spectrometry; angiogenesis was evaluated in tumor tissues [by microvessel counting and by investigating the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) proteins] as well as in human umbilical vein endothelial cells (HUVEC); cyclin D1 was evaluated by RT-PCR. MAGL and 2-AG were strongly expressed in tumor tissues. The MAGL inhibitor URB602 reduced xenograft tumor volume, this effect being associated to down-regulation of VEGF and FGF-2, reduction in the number of vessels and down-regulation of cyclin D1. In HUVEC, URB602 exerted a direct antiangiogenic effect by inhibiting FGF-2 induced proliferation and migration, and by modulating pro/anti-angiogenic agents. In experiments aiming at investigating the role of MAGL in chemoprevention, URB602 attenuated azoxymethane-induced preneoplastic lesions, polyps and tumors. MAGL, possibly through modulation of angiogenesis, plays a pivotal role in experimental colon carcinogenesis. Pharmacological inhibition of MAGL could represent an innovative therapeutic approach to reduce colorectal tumor progression.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Compostos de Bifenilo/uso terapêutico
Colo/efeitos dos fármacos
Neoplasias Colorretais/tratamento farmacológico
Inibidores Enzimáticos/uso terapêutico
Monoacilglicerol Lipases/antagonistas & inibidores
Reto/efeitos dos fármacos
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/uso terapêutico
Animais
Ácidos Araquidônicos/metabolismo
Carcinogênese/efeitos dos fármacos
Carcinogênese/genética
Carcinogênese/metabolismo
Carcinogênese/patologia
Linhagem Celular Tumoral
Colo/irrigação sanguínea
Colo/metabolismo
Colo/patologia
Neoplasias Colorretais/irrigação sanguínea
Neoplasias Colorretais/genética
Neoplasias Colorretais/patologia
Regulação para Baixo/efeitos dos fármacos
Endocanabinoides/metabolismo
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Glicerídeos/metabolismo
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Masculino
Camundongos Endogâmicos ICR
Camundongos Nus
Monoacilglicerol Lipases/genética
Monoacilglicerol Lipases/metabolismo
Neovascularização Patológica/tratamento farmacológico
Neovascularização Patológica/genética
Neovascularização Patológica/metabolismo
Neovascularização Patológica/patologia
Reto/irrigação sanguínea
Reto/metabolismo
Reto/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Antineoplastic Agents); 0 (Arachidonic Acids); 0 (Biphenyl Compounds); 0 (Endocannabinoids); 0 (Enzyme Inhibitors); 0 (Glycerides); 0 (URB602); 8D239QDW64 (glyceryl 2-arachidonate); EC 3.1.1.23 (Monoacylglycerol Lipases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170215
[St] Status:MEDLINE


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[PMID]:28088576
[Au] Autor:Riccardi L; Arencibia JM; Bono L; Armirotti A; Girotto S; De Vivo M
[Ad] Endereço:Laboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy. Electronic address: laura.riccardi@iit.it.
[Ti] Título:Lid domain plasticity and lipid flexibility modulate enzyme specificity in human monoacylglycerol lipase.
[So] Source:Biochim Biophys Acta;1862(5):441-451, 2017 05.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Human monoacylglycerol lipase (MAGL) is a membrane-interacting enzyme that generates pro-inflammatory signaling molecules. For this reason, MAGL inhibition is a promising strategy to treat pain, cancer, and neuroinflammatory diseases. MAGL can hydrolyze monoacylglycerols bearing an acyl chain of different lengths and degrees of unsaturation, cleaving primarily the endocannabinoid 2-arachidonoylglycerol. Importantly, the enzymatic binding site of MAGL is confined by a 75-amino-acid-long, flexible cap domain, named 'lid domain', which is structurally similar to that found in several other lipases. However, it is unclear how lid domain plasticity affects catalysis in MAGL. By integrating extensive molecular dynamics simulations and free-energy calculations with mutagenesis and kinetic experiments, we here define a lid-domain-mediated mechanism for substrate selection and binding in MAGL catalysis. In particular, we clarify the key role of Phe159 and Ile179, two conserved residues within the lid domain, in regulating substrate specificity in MAGL. We conclude by proposing that other structurally related lipases may share this lid-domain-mediated mechanism for substrate specificity.
[Mh] Termos MeSH primário: Monoacilglicerol Lipases/química
Monoacilglicerol Lipases/metabolismo
Monoglicerídeos/química
[Mh] Termos MeSH secundário: Catálise
Inibidores Enzimáticos/química
Seres Humanos
Cinética
Simulação de Dinâmica Molecular
Monoacilglicerol Lipases/genética
Monoglicerídeos/metabolismo
Ligação Proteica
Domínios Proteicos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Monoglycerides); EC 3.1.1.23 (Monoacylglycerol Lipases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170116
[St] Status:MEDLINE


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[PMID]:28086912
[Au] Autor:Tanaka M; Moran S; Wen J; Affram K; Chen T; Symes AJ; Zhang Y
[Ad] Endereço:Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
[Ti] Título:WWL70 attenuates PGE production derived from 2-arachidonoylglycerol in microglia by ABHD6-independent mechanism.
[So] Source:J Neuroinflammation;14(1):7, 2017 Jan 10.
[Is] ISSN:1742-2094
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: α/ß-Hydrolase domain 6 (ABHD6) is one of the major enzymes for endocannabinoid 2-arachidonoylglycerol (2-AG) hydrolysis in microglia cells. Our recent studies have shown that a selective ABHD6 inhibitor WWL70 has anti-inflammatory and neuroprotective effects in animal models of traumatic brain injury and multiple sclerosis. However, the role of ABHD6 in the neuroinflammatory response and the mechanisms by which WWL70 suppresses inflammation has not yet been elucidated in reactive microglia. METHODS: The hydrolytic activity and the levels of 2-AG in BV2 cells were measured by radioactivity assay and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The expression of cyclooxygenase-2 (COX-2) and prostaglandin E (PGE ) synthases in microglia treated with lipopolysaccharide (LPS) with/without WWL70 was determined by western blot and quantitative RT-PCR. The conversion of 2-AG to PGE or PGE -glyceryl ester (PGE -G) was assessed by enzyme-linked immunoassay (EIA) or LC-MS/MS. The involvement of ABHD6 in PGE production was assessed using pharmacological inhibitors and small interfering RNA (siRNA). The effect of WWL70 on PGE biosynthesis activity in the microsome fraction from BV2 cells and experimental autoimmune encephalopathy (EAE) mouse brain was also examined. RESULTS: We found that WWL70 suppressed PGE production in LPS-activated microglia via cannabinoid receptor-independent mechanisms, although intracellular levels of 2-AG were elevated by WWL70 treatment. This reduction was not attributable to WWL70 inhibition of ABHD6, given the fact that downregulation of ABHD6 by siRNA or use of KT182, an alternative ABHD6 inhibitor failed to suppress PGE production. WWL70 attenuated the expression of COX-2 and PGES-1/2 leading to the downregulation of the biosynthetic pathways of PGE and PGE -G. Moreover, PGE production from arachidonic acid was reduced in the microsome fraction, indicating that WWL70 also targets PGE biosynthetic enzymes, which are likely to contribute to the therapeutic mechanisms of WWL70 in the EAE mouse model. CONCLUSIONS: WWL70 is an anti-inflammatory therapeutic agent capable of inhibiting PGE and PGE -G production, primarily due to its reduction of COX-2 and microsomal PGES-1/2 expression and their PGE biosynthesis activity in microglia cells, as well as in the EAE mouse brain.
[Mh] Termos MeSH primário: Ácidos Araquidônicos/metabolismo
Compostos de Bifenilo/farmacologia
Carbamatos/farmacologia
Dinoprostona/metabolismo
Endocanabinoides/metabolismo
Inibidores Enzimáticos/farmacologia
Glicerídeos/metabolismo
Microglia/efeitos dos fármacos
Monoacilglicerol Lipases/metabolismo
[Mh] Termos MeSH secundário: Animais
Agonistas de Receptores de Canabinoides/farmacologia
Antagonistas de Receptores de Canabinoides/farmacologia
Células Cultivadas
Córtex Cerebral/citologia
Ciclo-Oxigenase 2/metabolismo
Dinoprostona/genética
Feminino
Hidrólise/efeitos dos fármacos
Lipopolissacarídeos/farmacologia
Masculino
Camundongos
Microglia/metabolismo
Piperidinas/farmacologia
Pirazóis/farmacologia
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arachidonic Acids); 0 (Biphenyl Compounds); 0 (Cannabinoid Receptor Agonists); 0 (Cannabinoid Receptor Antagonists); 0 (Carbamates); 0 (Endocannabinoids); 0 (Enzyme Inhibitors); 0 (Glycerides); 0 (Lipopolysaccharides); 0 (N-methyl-N-((3-(4-pyridinyl)phenyl)methyl)-4'-(aminocarbonyl)(1,1'-biphenyl)-4-yl ester, carbamic acid); 0 (Piperidines); 0 (Pyrazoles); 0 (RNA, Small Interfering); 8D239QDW64 (glyceryl 2-arachidonate); EC 1.14.99.1 (Cyclooxygenase 2); EC 3.1.1.23 (ABHD6 protein, mouse); EC 3.1.1.23 (Monoacylglycerol Lipases); K7Q1JQR04M (Dinoprostone); RML78EN3XE (rimonabant)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170115
[St] Status:MEDLINE
[do] DOI:10.1186/s12974-016-0783-4


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[PMID]:27890603
[Au] Autor:Guindon J
[Ad] Endereço:Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6592, Lubbock, TX, 794304, USA. Electronic address: josee.guindon@ttuhsc.edu.
[Ti] Título:A novel inhibitor of endocannabinoid catabolic enzymes sheds light on behind the scene interplay between chronic pain, analgesic tolerance, and heroin dependence.
[So] Source:Neuropharmacology;114:168-171, 2017 Mar 01.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:From the Aristotelian ancient Greece, pain has been associated with appetites or emotions and is opposite to pleasure. Reward and addiction is also linked to pleasure and compulsive drug seeking reinstates pleasure. Alleviation of chronic pain can induce a euphoric phase similar to what is found in addiction. Both chronic pain and addiction are recognized as a disease of the central nervous system. They share many characteristics and brain regions/mechanisms. Evidence points to the usefulness of cannabinoids as a new class of agents to add to the pharmaceutical toolbox in the management of chronic pain. Wilkerson and colleagues, in this issue, examine SA-57, an inhibitor of two different endocannabinoid catabolic enzymes FAAH and MAGL, demonstrating its analgesic effectiveness and morphine-sparing properties in a chronic pain model, as well as its ability to reduce heroin seeking behavior in a self-administration paradigm in mice. This timely study emphasizes the need for development of more efficacious chronic pain therapeutics with minimized abuse potential and/or reinforcing properties. It also highlights the need for better understanding of the overlapping circuitry of chronic pain, reward, and addiction.
[Mh] Termos MeSH primário: Endocanabinoides
Monoacilglicerol Lipases
[Mh] Termos MeSH secundário: Amidoidrolases
Analgésicos
Animais
Dor Crônica
Dependência de Heroína
Camundongos
Piperidinas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Endocannabinoids); 0 (Piperidines); EC 3.1.1.23 (Monoacylglycerol Lipases); EC 3.5.- (Amidohydrolases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161129
[St] Status:MEDLINE


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[PMID]:27766867
[Au] Autor:Tuo W; Leleu-Chavain N; Spencer J; Sansook S; Millet R; Chavatte P
[Ad] Endereço:Université de Lille, Inserm, CHU Lille, U995, LIRIC, Lille Inflammation Research International Center, F-59000 Lille, France.
[Ti] Título:Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors.
[So] Source:J Med Chem;60(1):4-46, 2017 Jan 12.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fatty acid ethanolamides (FAEs) and endocannabinoids (ECs) have been shown to alleviate pain and inflammation, regulate motility and appetite, and produce anticancer, anxiolytic, and neuroprotective efficacies via cannabinoid receptor type 1 (CB ) or type 2 (CB ) or via peroxisome proliferator-activated receptor α (PPAR-α) stimulation. FAEs and ECs are synthesized by a series of endogenous enzymes, including N-acylphosphatidylethanolaminephospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), or phospholipase C (PLC), and their metabolism is mediated by several metabolic enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), N-acylethanolamine acid amidase (NAAA), or cyclooxygenase 2 (COX-2). Over the past decades, increasing the concentration of FAEs and ECs through the inhibition of degrading enzymes has been considered to be a viable therapeutic approach to enhance their antinociceptive and anti-inflammatory effects, as well as to protect the nervous system.
[Mh] Termos MeSH primário: Amidoidrolases/antagonistas & inibidores
Amidoidrolases/uso terapêutico
Inibidores Enzimáticos/uso terapêutico
Monoacilglicerol Lipases/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Enzyme Inhibitors); EC 3.1.1.23 (Monoacylglycerol Lipases); EC 3.5.- (Amidohydrolases); EC 3.5.1.- (NAAA protein, human); EC 3.5.1.- (fatty-acid amide hydrolase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161022
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b00538



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