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[PMID]: 28401228 [Au] Autor: Davis CA; Erickson PR; McNeill K; Janssen EML [Ad] Endereço: Institute of Biogeochemistry and Pollutant Dynamics, ETH Zurich, 8092 Zurich, Switzerland. kris.mcneill@env.ethz.ch. [Ti] Título: Environmental photochemistry of fenamate NSAIDs and their radical intermediates. [So] Source: Environ Sci Process Impacts;19(5):656-665, 2017 May 24. [Is] ISSN: 2050-7895 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Fenamates are a class of nonsteroidal anti-inflammatory drugs (NSAIDs) that are not fully removed during wastewater treatment and can be released to surface waters. Here, near-surface photochemical half-lives were evaluated to range from minutes to hours of four fenamates and the closely related diclofenac. While quantum yields for direct photochemical reactions at the water surface vary widely from 0.071 for diclofenac to <0.001 for mefenamic acid, all fenamates showed significant reactivity towards singlet oxygen and hydroxyl radical with bimolecular reaction rate constants of 1.3-2.8 × 10 M s and 1.1-2.7 × 10 M s , respectively. Photodecay rates increased in the presence of dissolved organic matter (DOM) for diclofenac (+19%), tolfenamic acid (+9%), and mefenamic acid (+95%), but decreased for flufenamic acid (-2%) and meclofenamic acid (-14%) after accounting for light screening effects. Fast reaction rate constants of all NSAIDs with model triplet sensitizers were quantified by laser flash photolysis. Here, the direct observation of diphenylamine radical intermediates by transient absorption spectroscopy demonstrates one-electron oxidation of all fenamates. Quenching rate constants of these radical intermediates by ascorbic acid, a model antioxidant, were also quantified. These observations suggest that the balance of oxidation by photoexcited triplet DOM and quenching of the formed radical intermediates by antioxidant moieties determines whether net sensitization or net quenching by DOM occurs in the photochemical degradation of fenamates. [Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/análise Fenamatos/análise Substâncias Húmicas/análise Luz Poluentes Químicos da Água/análise [Mh] Termos MeSH secundário: Anti-Inflamatórios não Esteroides/química Anti-Inflamatórios não Esteroides/efeitos da radiação Recuperação e Remediação Ambiental Fenamatos/química Fenamatos/efeitos da radiação Água Doce/química Radical Hidroxila/química Modelos Teóricos Oxirredução Fotoquímica Oxigênio Singlete/química Análise Espectral Águas Residuais/química Poluentes Químicos da Água/química Poluentes Químicos da Água/efeitos da radiação [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Fenamates); 0 (Humic Substances); 0 (Waste Water); 0 (Water Pollutants, Chemical); 17778-80-2 (Singlet Oxygen); 3352-57-6 (Hydroxyl Radical) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170925 [Lr] Data última revisão: 170925 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170413 [St] Status: MEDLINE [do] DOI: 10.1039/c7em00079k

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[PMID]: 27226593 [Au] Autor: Orlando BJ; Malkowski MG [Ad] Endereço: From the Department of Structural Biology, The State University of New York at Buffalo and. [Ti] Título: Substrate-selective Inhibition of Cyclooxygeanse-2 by Fenamic Acid Derivatives Is Dependent on Peroxide Tone. [So] Source: J Biol Chem;291(29):15069-81, 2016 07 15. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Cyclooxygenase-2 (COX-2) catalyzes the oxygenation of arachidonic acid (AA) and endocannabinoid substrates, placing the enzyme at a unique junction between the eicosanoid and endocannabinoid signaling pathways. COX-2 is a sequence homodimer, but the enzyme displays half-of-site reactivity, such that only one monomer of the dimer is active at a given time. Certain rapid reversible, competitive nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit COX-2 in a substrate-selective manner, with the binding of inhibitor to a single monomer sufficient to inhibit the oxygenation of endocannabinoids but not arachidonic acid. The underlying mechanism responsible for substrate-selective inhibition has remained elusive. We utilized structural and biophysical methods to evaluate flufenamic acid, meclofenamic acid, mefenamic acid, and tolfenamic acid for their ability to act as substrate-selective inhibitors. Crystal structures of each drug in complex with human COX-2 revealed that the inhibitor binds within the cyclooxygenase channel in an inverted orientation, with the carboxylate group interacting with Tyr-385 and Ser-530 at the top of the channel. Tryptophan fluorescence quenching, continuous-wave electron spin resonance, and UV-visible spectroscopy demonstrate that flufenamic acid, mefenamic acid, and tolfenamic acid are substrate-selective inhibitors that bind rapidly to COX-2, quench tyrosyl radicals, and reduce higher oxidation states of the heme moiety. Substrate-selective inhibition was attenuated by the addition of the lipid peroxide 15-hydroperoxyeicosatertaenoic acid. Collectively, these studies implicate peroxide tone as an important mechanistic component of substrate-selective inhibition by flufenamic acid, mefenamic acid, and tolfenamic acid. [Mh] Termos MeSH primário: Inibidores de Ciclo-Oxigenase 2/química Inibidores de Ciclo-Oxigenase 2/farmacologia Ciclo-Oxigenase 2/metabolismo Fenamatos/farmacologia [Mh] Termos MeSH secundário: Substituição de Aminoácidos Sítios de Ligação Cristalografia por Raios X Ciclo-Oxigenase 2/química Ciclo-Oxigenase 2/genética Endocanabinoides/metabolismo Fenamatos/química Heme/química Seres Humanos Técnicas In Vitro Modelos Moleculares Mutagênese Sítio-Dirigida Peróxidos/metabolismo Proteínas Recombinantes/química Proteínas Recombinantes/genética Proteínas Recombinantes/metabolismo Especificidade por Substrato Triptofano/química [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Cyclooxygenase 2 Inhibitors); 0 (Endocannabinoids); 0 (Fenamates); 0 (Peroxides); 0 (Recombinant Proteins); 42VZT0U6YR (Heme); 8DUH1N11BX (Tryptophan); EC 1.14.99.1 (Cyclooxygenase 2); EC 1.14.99.1 (PTGS2 protein, human) [Em] Mês de entrada: 1704 [Cu] Atualização por classe: 170715 [Lr] Data última revisão: 170715 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160527 [St] Status: MEDLINE [do] DOI: 10.1074/jbc.M116.725713

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[PMID]: 26248795 [Au] Autor: Lee GS; Kappler K; Porter CJ; Scanlon MJ; Nicolazzo JA [Ad] Endereço: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences,, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia. [Ti] Título: Fatty Acid Binding Proteins Expressed at the Human Blood-Brain Barrier Bind Drugs in an Isoform-Specific Manner. [So] Source: Pharm Res;32(10):3432-46, 2015 Oct. [Is] ISSN: 1573-904X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: PURPOSE: To examine the expression of fatty acid binding proteins (FABPs) at the human blood-brain barrier (BBB) and to assess their ability to bind lipophilic drugs. METHODS: mRNA and protein expression of FABP subtypes in immortalized human brain endothelial (hCMEC/D3) cells were examined by RT-qPCR and Western blot, respectively. FABPs that were found in hCMEC/D3 cells (hFABPs) were recombinantly expressed and purified from Escherichia coli C41(DE3) cells. Drug binding to these hFABPs was assessed using a fluorescence assay, which measured the ability of a panel of lipophilic drugs to displace the fluorescent probe compound 1-anilinonaphthalene-8-sulfonic acid (ANS). RESULTS: hFABP3, 4 and 5 were expressed in hCMEC/D3 cells at the mRNA and protein level. The competitive ANS displacement assay demonstrated that, in general, glitazones preferentially bound to hFABP5 (Ki: 1.0-28 µM) and fibrates and fenamates preferentially bound to hFABP4 (Ki: 0.100-17 µM). In general, lipophilic drugs appeared to show weaker affinities for hFABP3 relative to hFABP4 and hFABP5. No clear correlation was observed between the molecular structure or physicochemical properties of the drugs and their ability to displace ANS from hFABP3, 4 and 5. CONCLUSIONS: hFABP3, 4 and 5 are expressed at the human BBB and bind differentially to a diverse range of lipophilic drugs. The unique expression and binding patterns of hFABPs at the BBB may therefore influence drug disposition into the brain. [Mh] Termos MeSH primário: Barreira Hematoencefálica/metabolismo Proteínas de Ligação a Ácido Graxo/metabolismo Preparações Farmacêuticas/metabolismo Ligação Proteica/fisiologia Isoformas de Proteínas/metabolismo [Mh] Termos MeSH secundário: Naftalenossulfonato de Anilina/metabolismo Transporte Biológico/fisiologia Encéfalo/metabolismo Linhagem Celular Células Endoteliais/metabolismo Fenamatos/metabolismo Ácidos Fíbricos/metabolismo Corantes Fluorescentes/metabolismo Seres Humanos RNA Mensageiro/metabolismo Tiazolidinedionas/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Anilino Naphthalenesulfonates); 0 (Fatty Acid-Binding Proteins); 0 (Fenamates); 0 (Fibric Acids); 0 (Fluorescent Dyes); 0 (Pharmaceutical Preparations); 0 (Protein Isoforms); 0 (RNA, Messenger); 0 (Thiazolidinediones); 630I4V6051 (1-anilino-8-naphthalenesulfonate) [Em] Mês de entrada: 1606 [Cu] Atualização por classe: 171031 [Lr] Data última revisão: 171031 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150808 [St] Status: MEDLINE [do] DOI: 10.1007/s11095-015-1764-5

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[PMID]: 25720865 [Au] Autor: Uzoh OG; Galek PT; Price SL [Ad] Endereço: Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK. s.l.price@ucl.ac.uk. [Ti] Título: Analysis of the conformational profiles of fenamates shows route towards novel, higher accuracy, force-fields for pharmaceuticals. [So] Source: Phys Chem Chem Phys;17(12):7936-48, 2015 Mar 28. [Is] ISSN: 1463-9084 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: In traditional molecular mechanics force fields, intramolecular non-bonded interactions are modelled as intermolecular interactions, and the form of the torsion potential is based on the conformational profiles of small organic molecules. We investigate how a separate model for the intramolecular forces in pharmaceuticals could be more realistic by analysing the low barrier to rotation of the phenyl ring in the fenamates (substituted N-phenyl-aminobenzoic acids), that results in a wide range of observed angles in the numerous fenamate crystal structures. Although the conformational energy changes by significantly less than 10 kJ mol(-1) for a complete rotation of the phenyl ring for fenamic acid, the barrier is only small because of small correlated changes in the other bond and torsion angles. The maxima for conformations where the two aromatic rings approach coplanarity arise from steric repulsion, but the maxima when the two rings are approximately perpendicular arise from a combination of an electronic effect and intramolecular dispersion. Representing the ab initio conformational energy profiles as a cosine series alone is ineffective; however, combining a cos 2ξ term to represent the electronic barrier with an intramolecular atom-atom exp-6 term for all atom pairs separated by three or more bonds (1-4 interactions) provides a very effective representation. Thus we propose a new, physically motivated, generic analytical model of conformational energy, which could be combined with an intermolecular model to form more accurate force-fields for modelling the condensed phases of pharmaceutical-like organic molecules. [Mh] Termos MeSH primário: Fenamatos/química Preparações Farmacêuticas/química [Mh] Termos MeSH secundário: Elétrons Conformação Molecular Simulação de Dinâmica Molecular Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Fenamates); 0 (Pharmaceutical Preparations) [Em] Mês de entrada: 1512 [Cu] Atualização por classe: 150312 [Lr] Data última revisão: 150312 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150228 [St] Status: MEDLINE [do] DOI: 10.1039/c4cp05525j

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[PMID]: 25522819 [Au] Autor: Alafeefy AM; Bakht MA; Ganaie MA; Ansarie MN; El-Sayed NN; Awaad AS [Ad] Endereço: Department of Pharmaceutical Chemistry, College of Pharmacy, Salman Bin Abdulaziz University, PO Box 173, Alkharj 11942, Saudi Arabia. Electronic address: a.alafeefy@sau.edu.sa. [Ti] Título: Synthesis, analgesic, anti-inflammatory and anti-ulcerogenic activities of certain novel Schiff's bases as fenamate isosteres. [So] Source: Bioorg Med Chem Lett;25(2):179-83, 2015 Jan 15. [Is] ISSN: 1464-3405 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: A series of certain novel Schiff bases as fenamate isosteres (VI:a-k) were synthesized to locate analgesic, anti-inflammatory agent with minimal ulcerogenic potential. The structures of the newly synthesized compounds were elucidated on the basis of their elemental analysis as well as IR, and NMR and mass spectroscopic data. All the compounds were evaluated for their anti-inflammatory activity by carrageenan induced paw oedema method. The compounds possessing good anti-inflammatory activity were further tested for analgesic, ulcerogenic, lipid peroxidation potentials and liver toxicity. Compounds (VI-c), (VI-f), (VI-h) and (VI-i) showed the best anti-inflammatory and significant analgesic activities at doses comparable to that of the standard drug Indomethacin. However, compounds (VI-c) and (VI-f) could be considered the most potent anti-inflammatory and analgesic molecules with maximum reduction in gastro-intestinal ulceration with no hepatocyte necrosis or liver degeneration. [Mh] Termos MeSH primário: Analgésicos/síntese química Anti-Inflamatórios/síntese química Antiulcerosos/síntese química Fenamatos/síntese química [Mh] Termos MeSH secundário: Analgésicos/uso terapêutico Animais Anti-Inflamatórios/uso terapêutico Antiulcerosos/uso terapêutico Edema/tratamento farmacológico Edema/patologia Fenamatos/uso terapêutico Masculino Camundongos Ratos Ratos Wistar Bases de Schiff/síntese química Bases de Schiff/uso terapêutico Estereoisomerismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Analgesics); 0 (Anti-Inflammatory Agents); 0 (Anti-Ulcer Agents); 0 (Fenamates); 0 (Schiff Bases) [Em] Mês de entrada: 1509 [Cu] Atualização por classe: 141226 [Lr] Data última revisão: 141226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 141220 [St] Status: MEDLINE

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[PMID]: 24509840 [Au] Autor: Veale EL; Al-Moubarak E; Bajaria N; Omoto K; Cao L; Tucker SJ; Stevens EB; Mathie A [Ad] Endereço: Medway School of Pharmacy, University of Kent, Chatham Maritime, Kent, United Kingdom (E.L.V., E.A.-M., N.B., A.M.); Pfizer Neusentis, Great Abington, Cambridge, United Kingdom (K.O., L.C., E.B.S.); and Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, United Kingdom (S.J.T.). [Ti] Título: Influence of the N terminus on the biophysical properties and pharmacology of TREK1 potassium channels. [So] Source: Mol Pharmacol;85(5):671-81, 2014 May. [Is] ISSN: 1521-0111 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: TWIK-related K(+) 1 (TREK1) potassium channels are members of the two-pore domain potassium channel family and contribute to background potassium conductances in many cell types, where their activity can be regulated by a variety of physiologic and pharmacologic mediators. Fenamates such as FFA (flufenamic acid; 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid), MFA [mefenamic acid; 2-(2,3-dimethylphenyl)aminobenzoic acid], NFA [niflumic acid; 2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid], and diclofenac [2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid] and the related experimental drug BL-1249 [(5,6,7,8-tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine] enhance the activity of TREK1 currents, and we show that BL-1249 is the most potent of these compounds. Alternative translation initiation produces a shorter, N terminus truncated form of TREK1 with a much reduced open probability and a proposed increased permeability to sodium compared with the longer form. We show that both forms of TREK1 can be activated by fenamates and that a number of mutations that affect TREK1 channel gating occlude the action of fenamates but only in the longer form of TREK1. Furthermore, fenamates produce a marked enhancement of current through the shorter, truncated form of TREK1 and reveal a K(+)-selective channel, like the long form. These results provide insight into the mechanism of TREK1 channel activation by fenamates, and, given the role of TREK1 channels in pain, they suggest a novel analgesic mechanism for these compounds. [Mh] Termos MeSH primário: Fenamatos/farmacologia Canais de Potássio de Domínios Poros em Tandem/agonistas Canais de Potássio de Domínios Poros em Tandem/fisiologia [Mh] Termos MeSH secundário: Células HEK293 Seres Humanos Ativação do Canal Iônico/efeitos dos fármacos Ativação do Canal Iônico/fisiologia Mutação/fisiologia Canais de Potássio de Domínios Poros em Tandem/química Estrutura Secundária de Proteína [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Fenamates); 0 (Potassium Channels, Tandem Pore Domain); 0 (potassium channel protein TREK-1) [Em] Mês de entrada: 1405 [Cu] Atualização por classe: 150708 [Lr] Data última revisão: 150708 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140211 [St] Status: MEDLINE [do] DOI: 10.1124/mol.113.091199

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[PMID]: 23656341 [Au] Autor: Cimolai N [Ad] Endereço: Department of Pathology and Laboratory Medicine, Children's and Women's Health Centre of British Columbia, Vancouver, BC, V6H 3V4, Canada. ncimolai@mail.ubc.ca [Ti] Título: The potential and promise of mefenamic acid. [So] Source: Expert Rev Clin Pharmacol;6(3):289-305, 2013 May. [Is] ISSN: 1751-2441 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Clinical use of mefenamic acid has generally declined in an era where other NSAID use has flourished. While having modes of action and general toxicities similar to other NSAIDs, mefenamic acid, as a member of the fenamates, nevertheless possesses some unique in vitro effects that have the potential to distinguish this agent from others. Use of this drug remains relevant for pain syndromes and some gynecological disorders, albeit with considerable competition from other NSAIDs. New basic science has considerably improved the understanding of the biochemistry of mefenamic acid. As well as maintaining its use in traditional settings, there is a tremendous potential for expanding the application of mefenamic acid to niche roles. [Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/farmacologia Ácido Mefenâmico/farmacologia Dor/tratamento farmacológico [Mh] Termos MeSH secundário: Anti-Inflamatórios não Esteroides/química Feminino Fenamatos/farmacologia Seres Humanos Ácido Mefenâmico/química [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Fenamates); 367589PJ2C (Mefenamic Acid) [Em] Mês de entrada: 1311 [Cu] Atualização por classe: 131121 [Lr] Data última revisão: 131121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 130510 [St] Status: MEDLINE [do] DOI: 10.1586/ecp.13.15

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[PMID]: 22954807 [Au] Autor: Jabeen S; Dines TJ; Leharne SA; Chowdhry BZ [Ad] Endereço: School of Science, University of Greenwich, Medway Campus, Chatham Maritime, Kent ME4 4TB, UK. [Ti] Título: Raman and IR spectroscopic studies of fenamates--conformational differences in polymorphs of flufenamic acid, mefenamic acid and tolfenamic acid. [So] Source: Spectrochim Acta A Mol Biomol Spectrosc;96:972-85, 2012 Oct. [Is] ISSN: 1873-3557 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Solid-state Raman and IR spectra of two polymorphic forms of each of three fenamates (flufenamic acid, mefenamic acid and tolfenamic acid) display subtle but highly reproducible differences. Many of these spectral differences can be ascribed to different conformations of these molecules, involving two of four possible orientations of one substituted benzene ring with respect to the other. Interpretation of the vibrational spectra in terms of conformational differences has been facilitated by DFT calculations at the B3LYP/cc-pVDZ level for each conformer. The calculated spectra are compared with the experimental spectra in order to identify the conformers present in two polymorphic forms in each case, and detailed band assignments are obtained from the DFT calculations. [Mh] Termos MeSH primário: Fenamatos/química Conformação Molecular Análise Espectral Raman [Mh] Termos MeSH secundário: Ácido Flufenâmico/química Ácido Mefenâmico/química Modelos Moleculares Teoria Quântica Espectrofotometria Infravermelho Termodinâmica Vibração ortoaminobenzoatos/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Fenamates); 0 (ortho-Aminobenzoates); 367589PJ2C (Mefenamic Acid); 3G943U18KM (tolfenamic acid); 60GCX7Y6BH (Flufenamic Acid) [Em] Mês de entrada: 1304 [Cu] Atualização por classe: 141120 [Lr] Data última revisão: 141120 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 120908 [St] Status: MEDLINE

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[PMID]: 22851714 [Au] Autor: Garg P; Sanguinetti MC [Ad] Endereço: Nora Eccles Harrison Cardiovascular Research and Training Institute, Department of Physiology, University of Utah, Salt Lake City, Utah 84112, USA. [Ti] Título: Structure-activity relationship of fenamates as Slo2.1 channel activators. [So] Source: Mol Pharmacol;82(5):795-802, 2012 Nov. [Is] ISSN: 1521-0111 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Niflumic acid, 2-{[3-(trifluoromethyl)phenyl]amino}pyridine-3-carboxylic acid (NFA), a nonsteroidal anti-inflammatory drug that blocks cyclooxygenase (COX), was shown previously to activate [Na(+)](i)-regulated Slo2.1 channels. In this study, we report that other fenamates, including flufenamic acid, mefenamic acid, tolfenamic acid, meclofenamic acid, and a phenyl acetic acid derivative, diclofenac, also are low-potency (EC(50) = 80 µM to 2.1 mM), partial agonists of human Slo2.1 channels heterologously expressed in Xenopus oocytes. Substituent analysis determined that N-phenylanthranilic acid was the minimal pharmacophore for fenamate activation of Slo2.1 channels. The effects of fenamates were biphasic, with an initial rapid activation phase followed by a slow phase of current inhibition. Ibuprofen, a structurally dissimilar COX inhibitor, did not activate Slo2.1. Preincubation of oocytes with ibuprofen did not significantly alter the effects of NFA, suggesting that neither channel activation nor inhibition is associated with COX activity. A point mutation (A278R) in the pore-lining S6 segment of Slo2.1 increased the sensitivity to activation and reduced the inhibition induced by NFA. Together, our results suggest that fenamates bind to two sites on Slo2.1 channels: an extracellular accessible site to activate and a cytoplasmic accessible site in the pore to inhibit currents. [Mh] Termos MeSH primário: Fenamatos/farmacologia Canais de Potássio/agonistas [Mh] Termos MeSH secundário: Animais Inibidores de Ciclo-Oxigenase/farmacologia Feminino Fenamatos/química Seres Humanos Ibuprofeno/farmacologia Técnicas In Vitro Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/agonistas Ácido Niflúmico/farmacologia Oócitos/efeitos dos fármacos Oócitos/fisiologia Técnicas de Patch-Clamp Mutação Puntual Bloqueadores dos Canais de Potássio/farmacologia Canais de Potássio/genética Relação Estrutura-Atividade Xenopus laevis ortoaminobenzoatos/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Cyclooxygenase Inhibitors); 0 (Fenamates); 0 (KCNMA1 protein, human); 0 (KCNT2 protein, human); 0 (Large-Conductance Calcium-Activated Potassium Channel alpha Subunits); 0 (Potassium Channel Blockers); 0 (Potassium Channels); 0 (ortho-Aminobenzoates); 4U5MP5IUD8 (Niflumic Acid); 952VN06WBB (fenamic acid); WK2XYI10QM (Ibuprofen) [Em] Mês de entrada: 1302 [Cu] Atualização por classe: 161019 [Lr] Data última revisão: 161019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 120802 [St] Status: MEDLINE [do] DOI: 10.1124/mol.112.079194

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[PMID]: 22646516 [Au] Autor: Chen GL; Zeng B; Eastmond S; Elsenussi SE; Boa AN; Xu SZ [Ad] Endereço: Centre for Cardiovascular and Metabolic Research, Hull York Medical School, University of Hull, Hull, UK. [Ti] Título: Pharmacological comparison of novel synthetic fenamate analogues with econazole and 2-APB on the inhibition of TRPM2 channels. [So] Source: Br J Pharmacol;167(6):1232-43, 2012 Nov. [Is] ISSN: 1476-5381 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND AND PURPOSE: Fenamate analogues, econazole and 2-aminoethoxydiphenyl borate (2-APB) are inhibitors of transient receptor potential melastatin 2 (TRPM2) channels and are used as research tools. However, these compounds have different chemical structures and therapeutic applications. Here we have investigated the pharmacological profile of TRPM2 channels by application of newly synthesized fenamate analogues and the existing channel blockers. EXPERIMENTAL APPROACH: Human TRPM2 channels in tetracycline-regulated pcDNA4/TO vectors were transfected into HEK293 T-REx cells and the expression was induced by tetracycline. Whole cell currents were recorded by patch-clamp techniques. Ca(2+) influx or release was monitored by fluorometry. KEY RESULTS: Flufenamic acid (FFA), mefenamic acid (MFA) and niflumic acid (NFA) concentration-dependently inhibited TRPM2 current with potency order FFA > MFA = NFA. Modification of the 2-phenylamino ring by substitution of the trifluoromethyl group in FFA with -CH(3), -F, -CF(3), -OCH(3), -OCH(2)CH(3), -COOH, and -NO(2) at various positions, reduced channel blocking potency. The conservative substitution of 3-CF(3) in FFA by -CH(3) (3-MFA), however, gave the most potent fenamate analogue with an IC(50) of 76 µM, comparable to that of FFA, but unlike FFA, had no effect on Ca(2+) release. 3-MFA and FFA inhibited the channel intracellularly. Econazole and 2-APB showed non-selectivity by altering cytosolic Ca(2+) movement. Econazole also evoked a non-selective current. CONCLUSION AND IMPLICATIONS: The fenamate analogue 3-MFA was more selective than other TRPM2 channel blockers. FFA, 2-APB and econazole should be used with caution as TRPM2 channel blockers, as these compounds can interfere with intracellular Ca(2+) movement. [Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/farmacologia Compostos de Boro/farmacologia Econazol/farmacologia Fenamatos/farmacologia Canais de Cátion TRPM/antagonistas & inibidores [Mh] Termos MeSH secundário: Cálcio/fisiologia Células HEK293 Seres Humanos [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Boron Compounds); 0 (Fenamates); 0 (TRPM Cation Channels); 0 (TRPM2 protein, human); 6Z1Y2V4A7M (Econazole); E4ES684O93 (2-aminoethoxydiphenyl borate); SY7Q814VUP (Calcium) [Em] Mês de entrada: 1303 [Cu] Atualização por classe: 161125 [Lr] Data última revisão: 161125 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 120601 [St] Status: MEDLINE [do] DOI: 10.1111/j.1476-5381.2012.02058.x

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