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[PMID]: 26572827 [Au] Autor: Cho KJ; van der Hoeven D; Zhou Y; Maekawa M; Ma X; Chen W; Fairn GD; Hancock JF [Ad] Endereço: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Medical School, Houston, Texas, USA. [Ti] Título: Inhibition of Acid Sphingomyelinase Depletes Cellular Phosphatidylserine and Mislocalizes K-Ras from the Plasma Membrane. [So] Source: Mol Cell Biol;36(2):363-74, 2015 Nov 16. [Is] ISSN: 1098-5549 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: K-Ras must localize to the plasma membrane for biological activity; thus, preventing plasma membrane interaction blocks K-Ras signal output. Here we show that inhibition of acid sphingomyelinase (ASM) mislocalizes both the K-Ras isoforms K-Ras4A and K-Ras4B from the plasma membrane to the endomembrane and inhibits their nanoclustering. We found that fendiline, a potent ASM inhibitor, reduces the phosphatidylserine (PtdSer) and cholesterol content of the inner plasma membrane. These lipid changes are causative because supplementation of fendiline-treated cells with exogenous PtdSer rapidly restores K-Ras4A and K-Ras4B plasma membrane binding, nanoclustering, and signal output. Conversely, supplementation with exogenous cholesterol restores K-Ras4A but not K-Ras4B nanoclustering. These experiments reveal different operational pools of PtdSer on the plasma membrane. Inhibition of ASM elevates cellular sphingomyelin and reduces cellular ceramide levels. Concordantly, delivery of recombinant ASM or exogenous ceramide to fendiline-treated cells rapidly relocalizes K-Ras4B and PtdSer to the plasma membrane. K-Ras4B mislocalization is also recapitulated in ASM-deficient Neimann-Pick type A and B fibroblasts. This study identifies sphingomyelin metabolism as an indirect regulator of K-Ras4A and K-Ras4B signaling through the control of PtdSer plasma membrane content. It also demonstrates the critical and selective importance of PtdSer to K-Ras4A and K-Ras4B plasma membrane binding and nanoscale spatial organization. [Mh] Termos MeSH primário: Membrana Celular/efeitos dos fármacos Inibidores Enzimáticos/farmacologia Fendilina/farmacologia Fosfatidilserinas/metabolismo Esfingomielina Fosfodiesterase/antagonistas & inibidores Esfingomielina Fosfodiesterase/metabolismo Proteínas ras/metabolismo [Mh] Termos MeSH secundário: Animais Linhagem Celular Membrana Celular/metabolismo Colesterol/metabolismo Cricetinae Cães Seres Humanos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Enzyme Inhibitors); 0 (Phosphatidylserines); 97C5T2UQ7J (Cholesterol); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase); EC 3.6.5.2 (ras Proteins); S253D559A8 (Fendiline) [Em] Mês de entrada: 1605 [Cu] Atualização por classe: 170916 [Lr] Data última revisão: 170916 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 151118 [St] Status: MEDLINE [do] DOI: 10.1128/MCB.00719-15

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[PMID]: 26440150 [Au] Autor: Woods N; Trevino J; Coppola D; Chellappan S; Yang S; Padmanabhan J [Ad] Endereço: Department of Molecular Medicine, University of South Florida, Tampa, FL, USA. [Ti] Título: Fendiline inhibits proliferation and invasion of pancreatic cancer cells by interfering with ADAM10 activation and ß-catenin signaling. [So] Source: Oncotarget;6(34):35931-48, 2015 Nov 03. [Is] ISSN: 1949-2553 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: ADAM10 (A Disintegrin and Metalloprotease Domain 10) affects the pathophysiology of various cancers, and we had shown that inhibition of ADAM10 sensitizes pancreatic cancer cells to gemcitabine. ADAM10 is activated in response to calcium influx, and here we examined if calcium channel blockers (CCB) would impede ADAM10 activation and affect biology of pancreatic cancer cells. We find that the CCB, fendiline, significantly reduces proliferation, migration, invasion, and anchorage independent growth of pancreatic cancer cells. This was associated with ADAM10 inhibition and its localization at the actin-rich membrane protrusions. Further, fendiline-treated cells formed cadherin-catenin positive tight adherens junctions and elicited defective protein trafficking and recycling. Furthermore, the expression of ß-catenin target genes, cyclinD1, c-Myc and CD44, were significantly decreased, suggesting that fendiline might prevent cell proliferation and migration by inhibiting ADAM10 function, cadherin proteolysis and stabilization of cadherin-catenin interaction at the plasma membrane. This will subsequently diminish ß-catenin intracellular signaling and repress TCF/LEF target gene expression. Supporting this notion, RNAi-directed downregulation of ADAM10 in cancer cells decreased the expression of cyclinD1, c-Myc and CD44. Furthermore, analysis of human pancreatic tumor tissue microarrays and lysates showed elevated levels of ADAM10, suggesting that aberrant activation of ADAM10 plays a fundamental role in growth and metastasis of PDACs and inhibiting this pathway might be a viable strategy to combat PDACs. [Mh] Termos MeSH primário: Proteínas ADAM/antagonistas & inibidores Proteínas ADAM/metabolismo Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores Secretases da Proteína Precursora do Amiloide/metabolismo Fendilina/farmacologia Proteínas de Membrana/antagonistas & inibidores Proteínas de Membrana/metabolismo Neoplasias Pancreáticas/tratamento farmacológico beta Catenina/metabolismo [Mh] Termos MeSH secundário: Proteínas ADAM/genética Proteína ADAM10 Secretases da Proteína Precursora do Amiloide/genética Bloqueadores dos Canais de Cálcio/farmacologia Linhagem Celular Tumoral Movimento Celular/efeitos dos fármacos Proliferação Celular/efeitos dos fármacos Seres Humanos Proteínas de Membrana/genética Neoplasias Pancreáticas/genética Neoplasias Pancreáticas/metabolismo Neoplasias Pancreáticas/patologia Transdução de Sinais/efeitos dos fármacos Transfecção [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Calcium Channel Blockers); 0 (Membrane Proteins); 0 (beta Catenin); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.24.- (ADAM Proteins); EC 3.4.24.81 (ADAM10 Protein); EC 3.4.24.81 (ADAM10 protein, human); S253D559A8 (Fendiline) [Em] Mês de entrada: 1610 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 151007 [St] Status: MEDLINE [do] DOI: 10.18632/oncotarget.5933

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[PMID]: 26345344 [Au] Autor: Cunningham JJ; Orr E; Lothian BC; Morgen J; Brebner K [Ad] Endereço: Department of Psychiatry, University of British Columbia, Detwiller Pavilion, 2255 Wesbrook Mall, Vancouver, British Columbia, V6T 2A1, Canada. Jcunningham@alumni.ubc.ca. [Ti] Título: Effects of fendiline on cocaine-seeking behavior in the rat. [So] Source: Psychopharmacology (Berl);232(24):4401-10, 2015 Dec. [Is] ISSN: 1432-2072 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: RATIONALE: L-type Ca(2+) channels (LTCC) and GABAB receptors are both possible targets in the development of new pharmacological compounds for cocaine addiction. Drugs that target either receptor attenuate a wide range of cocaine-seeking behaviors in the rat. However, there is no current human-approved pharmacotherapeutic intervention for psychostimulant addiction. OBJECTIVES: This study examined the effects of a human-approved LTCC blocker, fendiline, on cocaine-taking and cocaine-seeking behavior in rats. The effects of combining fendiline with the GABAB receptor agonist baclofen on cocaine self-administration were also tested. METHODS: Male Wistar rats were trained to self-administer cocaine, and the effects of fendiline pretreatment (vehicle, 1.78, 3.16, 5.62 mg/kg, intraperitoneal (IP)) were tested on progressive ratio responding and cue- and drug-induced reinstatement. The effects of baclofen (vehicle, 0.56, 1.78, 3.16, 5.62 mg/kg, IP) combined with fendiline (5.62 mg/kg, IP) were tested on progressive ratio responding. Control experiments measured locomotor activity and lever pressing for food in rats that received both baclofen and fendiline prior to the test session. RESULTS: Acute injections of fendiline prior to cue- or drug-induced reinstatement significantly attenuated lever-pressing behavior (p < 0.05). Fendiline and baclofen, but not fendiline alone, not only significantly attenuated breakpoints, but also impaired general motor behavior and naturalistic reinforcement (p < 0.05). CONCLUSION: These data suggest that the LTCC blocker fendiline may represent a novel pharmacotherapeutic intervention to prevent reinstatement to cocaine seeking. Also, co-administration of fendiline and baclofen not only can attenuate the motivation to take cocaine, but also impairs general motor behavior and naturalistic reinforcement. [Mh] Termos MeSH primário: Bloqueadores dos Canais de Cálcio/farmacologia Estimulantes do Sistema Nervoso Central/administração & dosagem Cocaína/administração & dosagem Comportamento de Procura de Droga/efeitos dos fármacos Fendilina/farmacologia [Mh] Termos MeSH secundário: Animais Baclofeno/farmacologia Comportamento Aditivo/tratamento farmacológico Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico Sinais (Psicologia) Extinção Psicológica/efeitos dos fármacos Masculino Atividade Motora/efeitos dos fármacos Ratos Ratos Wistar Reforço (Psicologia) Autoadministração [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Calcium Channel Blockers); 0 (Central Nervous System Stimulants); H789N3FKE8 (Baclofen); I5Y540LHVR (Cocaine); S253D559A8 (Fendiline) [Em] Mês de entrada: 1606 [Cu] Atualização por classe: 170920 [Lr] Data última revisão: 170920 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150909 [St] Status: MEDLINE [do] DOI: 10.1007/s00213-015-4061-4

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[PMID]: 25532838 [Au] Autor: Lee GR; Hyun MH [Ad] Endereço: Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan 690-735, Korea. lgr8969@pusan.ac.kr. [Ti] Título: Liquid chromatographic resolution of fendiline and its analogues on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. [So] Source: Molecules;19(12):21386-97, 2014 Dec 19. [Is] ISSN: 1420-3049 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: Fendiline, an effective anti-anginal drug for the treatment of coronary heart diseases, and its sixteen analogues were resolved on a CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. Fendiline was resolved quite well with the separation factor (α) of 1.25 and resolution (RS) of 1.55 when a mobile phase consisting of methanol-acetonitrile-trifluoroacetic acid-triethylamine at a ratio of 80/20/0.1/0.5 (v/v/v/v) was used. The comparison of the chromatographic behaviors for the resolution of fendiline and its analogues indicated that the 3,3-diphenylpropyl group bonded to the secondary amino group of fendiline is important in the chiral recognition and the difference in the steric bulkiness between the phenyl group and the methyl group at the chiral center of fendiline is also important in the chiral recognition. [Mh] Termos MeSH primário: Fármacos Cardiovasculares/isolamento & purificação Éteres de Coroa/química Fendilina/análogos & derivados Fendilina/isolamento & purificação [Mh] Termos MeSH secundário: Acetonitrilos/química Cromatografia Líquida Etilaminas/química Metanol/química Solventes/química Ácido Trifluoracético/química [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Acetonitriles); 0 (Cardiovascular Agents); 0 (Crown Ethers); 0 (Ethylamines); 0 (Solvents); 119719-58-3 (18-crown-6 2,3,11,12-tetracarboxylic acid); E5R8Z4G708 (Trifluoroacetic Acid); S253D559A8 (Fendiline); VOU728O6AY (triethylamine); Y4S76JWI15 (Methanol); Z072SB282N (acetonitrile) [Em] Mês de entrada: 1508 [Cu] Atualização por classe: 141223 [Lr] Data última revisão: 141223 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 141224 [St] Status: MEDLINE [do] DOI: 10.3390/molecules191221386

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[PMID]: 24264565 [Au] Autor: Voigt RM; Riddle JL; Napier TC [Ad] Endereço: Department of Pharmacology, Rush University Medical Center, Cohn Research Building, 1735 W Harrison St., Suite #424, Chicago, IL, 60612, USA, robin_voigt@rush.edu. [Ti] Título: Effect of fendiline on the maintenance and expression of methamphetamine-induced conditioned place preference in Sprague-Dawley rats. [So] Source: Psychopharmacology (Berl);231(9):2019-29, 2014 May. [Is] ISSN: 1432-2072 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: RATIONALE: Fendiline is a GABAB receptor-positive allosteric modulator and L-type Ca²â�º channel blocker that is safe for human use. Based on these pharmacological properties, fendiline may be useful to disrupt associative memories that can drive relapse to drug use in drug-addicted individuals OBJECTIVE: The current study evaluated the potential of fendiline to inhibit the maintenance and expression of learned associations between methamphetamine (meth) and an environmental context using conditioned place preference (CPP) in rats, to model for the associative learning that occurs during drug abuse by humans METHODS: Following meth conditioning (1 mg/kg), fendiline (5 mg/kg) was administered at various post-conditioning times to ascertain if there was a temporal window during which fendiline would be effective. RESULTS: Two once-daily injections of fendiline did not influence the maintenance of CPP regardless of the post-conditioning treatment time while 10 once-daily fendiline treatments inhibited CPP maintenance (p < 0.05). Fendiline administered immediately prior to the CPP test inhibited expression of meth-induced CPP in rats with a fendiline treatment history of 10 once-daily injections (p < 0.05) or those that received two injections that corresponded to the last 2 days of the 10-day treatment (p < 0.05). Fendiline did not produce preference or aversion on its own, nor did it alter motivated motor behavior. CONCLUSION: Maintenance and expression of meth CPP is mitigated by repeated fendiline treatments when administered during the days that precede CPP testing. Reduction in the significance of meth-associated cues can reduce relapse; therefore, fendiline may be of value for addiction therapy in abstinent, meth-addicted humans. [Mh] Termos MeSH primário: Bloqueadores dos Canais de Cálcio/farmacologia Estimulantes do Sistema Nervoso Central/farmacologia Condicionamento (Psicologia)/efeitos dos fármacos Fendilina/farmacologia Metanfetamina/farmacologia Percepção Espacial/efeitos dos fármacos [Mh] Termos MeSH secundário: Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico Animais Aprendizagem por Associação/efeitos dos fármacos Aprendizagem da Esquiva/efeitos dos fármacos Masculino Memória/efeitos dos fármacos Atividade Motora/efeitos dos fármacos Ratos Sprague-Dawley Teste de Desempenho do Rota-Rod Fatores de Tempo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Calcium Channel Blockers); 0 (Central Nervous System Stimulants); 44RAL3456C (Methamphetamine); S253D559A8 (Fendiline) [Em] Mês de entrada: 1412 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 131123 [St] Status: MEDLINE [do] DOI: 10.1007/s00213-013-3347-7

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[PMID]: 23129805 [Au] Autor: van der Hoeven D; Cho KJ; Ma X; Chigurupati S; Parton RG; Hancock JF [Ad] Endereço: Department of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, Houston, Texas, USA. [Ti] Título: Fendiline inhibits K-Ras plasma membrane localization and blocks K-Ras signal transmission. [So] Source: Mol Cell Biol;33(2):237-51, 2013 Jan. [Is] ISSN: 1098-5549 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Ras proteins regulate signaling pathways important for cell growth, differentiation, and survival. Oncogenic mutant Ras proteins are commonly expressed in human tumors, with mutations of the K-Ras isoform being most prevalent. To be active, K-Ras must undergo posttranslational processing and associate with the plasma membrane. We therefore devised a high-content screening assay to search for inhibitors of K-Ras plasma membrane association. Using this assay, we identified fendiline, an L-type calcium channel blocker, as a specific inhibitor of K-Ras plasma membrane targeting with no detectable effect on the localization of H- and N-Ras. Other classes of L-type calcium channel blockers did not mislocalize K-Ras, suggesting a mechanism that is unrelated to calcium channel blockade. Fendiline did not inhibit K-Ras posttranslational processing but significantly reduced nanoclustering of K-Ras and redistributed K-Ras from the plasma membrane to the endoplasmic reticulum (ER), Golgi apparatus, endosomes, and cytosol. Fendiline significantly inhibited signaling downstream of constitutively active K-Ras and endogenous K-Ras signaling in cells transformed by oncogenic H-Ras. Consistent with these effects, fendiline blocked the proliferation of pancreatic, colon, lung, and endometrial cancer cell lines expressing oncogenic mutant K-Ras. Taken together, these results suggest that inhibitors of K-Ras plasma membrane localization may have utility as novel K-Ras-specific anticancer therapeutics. [Mh] Termos MeSH primário: Bloqueadores dos Canais de Cálcio/farmacologia Membrana Celular/efeitos dos fármacos Fendilina/farmacologia Proteínas Proto-Oncogênicas/metabolismo Transdução de Sinais/efeitos dos fármacos Proteínas ras/metabolismo [Mh] Termos MeSH secundário: Animais Western Blotting Linhagem Celular Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Sobrevivência Celular/efeitos dos fármacos Cães Retículo Endoplasmático/metabolismo Endossomos/metabolismo Complexo de Golgi/metabolismo Seres Humanos Células Madin Darby de Rim Canino Metilação Microscopia de Fluorescência Mutação Isoformas de Proteínas/genética Isoformas de Proteínas/metabolismo Proteínas Proto-Oncogênicas/genética Proteínas Proto-Oncogênicas p21(ras) Proteínas ras/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Calcium Channel Blockers); 0 (KRAS protein, human); 0 (Protein Isoforms); 0 (Proto-Oncogene Proteins); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)); EC 3.6.5.2 (ras Proteins); S253D559A8 (Fendiline) [Em] Mês de entrada: 1302 [Cu] Atualização por classe: 161125 [Lr] Data última revisão: 161125 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 121107 [St] Status: MEDLINE [do] DOI: 10.1128/MCB.00884-12

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[PMID]: 23011467 [Au] Autor: Yamamoto R; Matsushita M; Kitoh H; Masuda A; Ito M; Katagiri T; Kawai T; Ishiguro N; Ohno K [Ad] Endereço: Department of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550, Japan. [Ti] Título: Clinically applicable antianginal agents suppress osteoblastic transformation of myogenic cells and heterotopic ossifications in mice. [So] Source: J Bone Miner Metab;31(1):26-33, 2013 Jan. [Is] ISSN: 1435-5604 [Cp] País de publicação: Japan [La] Idioma: eng [Ab] Resumo: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by progressive heterotopic ossification. FOP is caused by a gain-of-function mutation in ACVR1 encoding the bone morphogenetic protein type II receptor, ACVR1/ALK2. The mutant receptor causes upregulation of a transcriptional factor, Id1. No therapy is available to prevent the progressive heterotopic ossification in FOP. In an effort to search for clinically applicable drugs for FOP, we screened 1,040 FDA-approved drugs for suppression of the Id1 promoter activated by the mutant ACVR1/ALK2 in C2C12 cells. We found that that two antianginal agents, fendiline hydrochloride and perhexiline maleate, suppressed the Id1 promoter in a dose-dependent manner. The drugs also suppressed the expression of native Id1 mRNA and alkaline phosphatase in a dose-dependent manner. Perhexiline but not fendiline downregulated phosphorylation of Smad 1/5/8 driven by bone morphogenetic protein (BMP)-2. We implanted crude BMPs in muscles of ddY mice and fed them fendiline or perhexiline for 30 days. Mice taking perhexiline showed a 38.0 % reduction in the volume of heterotopic ossification compared to controls, whereas mice taking fendiline showed a slight reduction of heterotopic ossification. Fendiline, perhexiline, and their possible derivatives are potentially applicable to clinical practice to prevent devastating heterotopic ossification in FOP. [Mh] Termos MeSH primário: Bloqueadores dos Canais de Cálcio/farmacologia Fendilina/farmacologia Células Musculares/metabolismo Miosite Ossificante/tratamento farmacológico Ossificação Heterotópica/tratamento farmacológico Osteoblastos/metabolismo Perexilina/análogos & derivados [Mh] Termos MeSH secundário: Receptores de Ativinas Tipo I/genética Receptores de Ativinas Tipo I/metabolismo Animais Proteína Morfogenética Óssea 2/genética Proteína Morfogenética Óssea 2/metabolismo Linhagem Celular Relação Dose-Resposta a Droga Avaliação Pré-Clínica de Medicamentos Proteína 1 Inibidora de Diferenciação/biossíntese Proteína 1 Inibidora de Diferenciação/genética Camundongos Camundongos Mutantes Células Musculares/patologia Mutação Miosite Ossificante/genética Miosite Ossificante/metabolismo Miosite Ossificante/patologia Ossificação Heterotópica/metabolismo Ossificação Heterotópica/patologia Osteoblastos/patologia Perexilina/farmacologia Regiões Promotoras Genéticas/genética Proteínas Smad/genética Proteínas Smad/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Bmp2 protein, mouse); 0 (Bone Morphogenetic Protein 2); 0 (Calcium Channel Blockers); 0 (Idb1 protein, mouse); 0 (Inhibitor of Differentiation Protein 1); 0 (Smad Proteins); EC 2.7.11.30 (Activin Receptors, Type I); EC 2.7.11.30 (Acvr1 protein, mouse); K7V8Y90G0H (perhexiline maleate); KU65374X44 (Perhexiline); S253D559A8 (Fendiline) [Em] Mês de entrada: 1306 [Cu] Atualização por classe: 171013 [Lr] Data última revisão: 171013 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 120927 [St] Status: MEDLINE [do] DOI: 10.1007/s00774-012-0380-2

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[PMID]: 22006241 [Au] Autor: Varesio E; Le Blanc JC; Hopfgartner G [Ad] Endereço: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Life Sciences Mass Spectrometry, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland. emmanuel.varesio@unige.ch [Ti] Título: Real-time 2D separation by LC × differential ion mobility hyphenated to mass spectrometry. [So] Source: Anal Bioanal Chem;402(8):2555-64, 2012 Mar. [Is] ISSN: 1618-2650 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: The liquid chromatography-mass spectrometry (LC-MS) analysis of complex samples such as biological fluid extracts is widespread when searching for new biomarkers as in metabolomics. The success of this hyphenation resides in the orthogonality of both separation techniques. However, there are frequent cases where compounds are co-eluting and the resolving power of mass spectrometry (MS) is not sufficient (e.g., isobaric compounds and interfering isotopic clusters). Different strategies are discussed to solve these cases and a mixture of eight compounds (i.e., bromazepam, chlorprothixene, clonapzepam, fendiline, flusilazol, oxfendazole, oxycodone, and pamaquine) with identical nominal mass (i.e., m/z 316) is taken to illustrate them. Among the different approaches, high-resolution mass spectrometry or liquid chromatography (i.e., UHPLC) can easily separate these compounds. Another technique, mostly used with low resolving power MS analyzers, is differential ion mobility spectrometry (DMS), where analytes are gas-phase separated according to their size-to-charge ratio. Detailed investigations of the addition of different polar modifiers (i.e., methanol, ethanol, and isopropanol) into the transport gas (nitrogen) to enhance the peak capacity of the technique were carried out. Finally, a complex urine sample fortified with 36 compounds of various chemical properties was analyzed by real-time 2D separation LC×DMS-MS(/MS). The addition of this orthogonal gas-phase separation technique in the LC-MS(/MS) hyphenation greatly improved data quality by resolving composite MS/MS spectra, which is mandatory in metabolomics when performing database generation and search. [Mh] Termos MeSH primário: Espectrometria de Massas [Mh] Termos MeSH secundário: Aminoquinolinas/urina Benzimidazóis/urina Bromazepam/urina Clorprotixeno/urina Cromatografia Líquida de Alta Pressão Clonazepam/urina Fendilina/urina Seres Humanos Oxicodona/urina Silanos/urina Fatores de Tempo Triazóis/urina [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Aminoquinolines); 0 (Benzimidazoles); 0 (Silanes); 0 (Triazoles); 5PE9FDE8GB (Clonazepam); 99QVL5KPSU (pamaquine); 9S7OD60EWP (Chlorprothixene); CD35PMG570 (Oxycodone); F3WG2VVD87 (flusilazole); OMP2H17F9E (oxfendazole); S253D559A8 (Fendiline); X015L14V0O (Bromazepam) [Em] Mês de entrada: 1206 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 111019 [St] Status: MEDLINE [do] DOI: 10.1007/s00216-011-5444-y

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[PMID]: 19411560 [Au] Autor: Huang C; Huang C; Cheng J; Liu S; Chen I; Tsai J; Chou C; Tseng P; Jan C [Ad] Endereço: Department of Nursery, Tzu Hui Institute of Technology; Pingtung, Taiwan. [Ti] Título: Fendiline-evoked [Ca2+]i rises and non-Ca2+-triggered cell death in human oral cancer cells. [So] Source: Hum Exp Toxicol;28(1):41-8, 2009 Jan. [Is] ISSN: 0960-3271 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The effect of fendiline on cytosolic free Ca(2+) concentrations ([Ca(2+)](i)) and proliferation has not been explored in human oral cancer cells. This study examined whether fendiline altered Ca(2+) levels and caused cell death in OC2 human oral cancer cells. [Ca(2+)](i) and cell viability were measured using the fluorescent dyes fura-2 and WST-1, respectively. Fendiline at concentrations above 10 microM increased [Ca(2+)](i) in a concentration-dependent manner. The Ca(2+) signal was reduced partly by removing extracellular Ca(2+). The fendiline-induced Ca(2+) influx was sensitive to blockade of L-type Ca(2+) channel blockers. In Ca(2+)-free medium, after pretreatment with 50 microM fendiline, 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor)-induced [Ca(2+)](i) rises were inhibited; and conversely, thapsigargin pretreatment nearly abolished fendiline-induced [Ca(2+)](i) rises. Inhibition of phospholipase C with 2 microM U73122 did not change fendiline-induced [Ca(2+)](i) rises. At concentrations between 5 and 25 microM, fendiline killed cells in a concentration-dependent manner. The cytotoxic effect of 15 microM fendiline was not reversed by prechelating cytosolic Ca(2+) with BAPTA/AM. Collectively, in OC2 cells, fendiline induced [Ca(2+)](i) rises by causing Ca(2+) release from the endoplasmic reticulum and Ca(2+) influx from L-type Ca(2+) channels. Furthermore, fendiline-caused cytotoxicity was not via a preceding [Ca(2+)](i) rise. [Mh] Termos MeSH primário: Bloqueadores dos Canais de Cálcio/farmacologia Cálcio/metabolismo Fendilina/farmacologia Neoplasias Bucais/metabolismo Neoplasias Bucais/patologia [Mh] Termos MeSH secundário: Sinalização do Cálcio/efeitos dos fármacos Morte Celular/efeitos dos fármacos Linhagem Celular Tumoral Sobrevivência Celular/efeitos dos fármacos Relação Dose-Resposta a Droga Interações Medicamentosas Ácido Egtázico/análogos & derivados Ácido Egtázico/farmacologia Estrenos/farmacologia Corantes Fluorescentes/metabolismo Fura-2/metabolismo Seres Humanos Neoplasias Bucais/tratamento farmacológico Nifedipino/toxicidade Inibidores de Fosfodiesterase/farmacologia Pirrolidinonas/farmacologia Sais de Tetrazólio/metabolismo Tapsigargina/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium); 0 (Calcium Channel Blockers); 0 (Estrenes); 0 (Fluorescent Dyes); 0 (Phosphodiesterase Inhibitors); 0 (Pyrrolidinones); 0 (Tetrazolium Salts); 112648-68-7 (1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione); 526U7A2651 (Egtazic Acid); 67526-95-8 (Thapsigargin); I9ZF7L6G2L (Nifedipine); K22DDW77C0 (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid); S253D559A8 (Fendiline); SY7Q814VUP (Calcium); TSN3DL106G (Fura-2) [Em] Mês de entrada: 0906 [Cu] Atualização por classe: 131121 [Lr] Data última revisão: 131121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 090505 [St] Status: MEDLINE [do] DOI: 10.1177/0960327108097436

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MEDLINE

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[PMID]: 18459732 [Au] Autor: Kövesi I; Menyhárd DK; Laberge M; Fidy J [Ad] Endereço: Department of Biophysics and Radiation Biology and Research Group for Membrane Biology, Hungarian Academy of Sciences, Faculty of Medicine, Semmelweis University, Budapest, Hungary. [Ti] Título: Interaction of antagonists with calmodulin: insights from molecular dynamics simulations. [So] Source: J Med Chem;51(11):3081-93, 2008 Jun 12. [Is] ISSN: 0022-2623 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: We report results of 12 ns, all-atom molecular dynamics simulation (MDS) and Poisson-Boltzmann free energy calculations (PBFE) on calmodulin (CaM) bound to two molecules of trifluoperazine (TFP) and of N-(3,3, diphenylpropyl)- N'-[1- R-(3,4-bis-butoxyphenyl)-ethyl]-propylenediamine (DPD). X-ray data show very similar structures for the two complexes, yet the antagonists significantly differ with respect to their CaM binding affinities, the neutral DPD is much more potent. The goal of the study was to unravel the reason why TFP is less potent although its positive charge should facilitate binding. The electrostatic energy terms in CHARMM and binding free energy terms of the PBFE approach showed TFP a better antagonist, while inspection of hydrophobic contacts supports DPD binding. Detailed inspection of the amino acid contributions of PBFE calculations unravel that steric reasons oppose the favorable binding of TFP. Structural conditions are given for a successful drug design strategy, which may benefit also from charge-charge interactions. [Mh] Termos MeSH primário: Calmodulina/antagonistas & inibidores Calmodulina/química Fendilina/análogos & derivados Modelos Moleculares Trifluoperazina/química [Mh] Termos MeSH secundário: Sítios de Ligação Simulação por Computador Fendilina/química Interações Hidrofóbicas e Hidrofílicas Estrutura Molecular Ligação Proteica Eletricidade Estática Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Calmodulin); 0 (N-(3,3-diphenylpropyl)-N'-(1-(3,4-bis(butoxyphenyl))ethyl)propylenediamine); 214IZI85K3 (Trifluoperazine); S253D559A8 (Fendiline) [Em] Mês de entrada: 0807 [Cu] Atualização por classe: 131121 [Lr] Data última revisão: 131121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 080508 [St] Status: MEDLINE [do] DOI: 10.1021/jm701406e

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