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[PMID]: 29287249 [Au] Autor: Pati ML; Niso M; Spitzer D; Berardi F; Contino M; Riganti C; Hawkins WG; Abate C [Ad] Endereço: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125 Bari, Italy; Department of Surgery, Division of Hepatobiliary, Pancreatic, and Gastrointestinal Surgery, Washington University School of Medicine, St. Louis, MO, USA. [Ti] Título: Multifunctional thiosemicarbazones and deconstructed analogues as a strategy to study the involvement of metal chelation, Sigma-2 (σ ) receptor and P-gp protein in the cytotoxic action: In vitro and in vivo activity in pancreatic tumors. [So] Source: Eur J Med Chem;144:359-371, 2018 Jan 20. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: The aggressiveness of pancreatic cancer urgently requires more efficient treatment options. Because the sigma-2 (σ ) receptor was recently proposed as a promising target for pancreatic cancer therapy, we explored our previously developed multifunctional thiosemicarbazones, designed to synergistically impair cell energy levels, by targeting σ and P-gp proteins and chelating Iron. A deconstruction approach was herein applied by removing one function at a time from the potent multifunctional thiosemicarbazones 1 and 2, to investigate the contribution to cytotoxicity of each target involved. The results from in vitro (panel of pancreatic tumor cells) and in vivo experiments (C57BL/6 bearing KP02 tumor), suggest that while the multifunctional activity was not required for the antitumor activity of these thiosemicarbazones, σ -targeting appeared to allow alternative tumor cell death mechanisms, leading to potent and less toxic off-targets toxicities compared to other thiosemicarbazones devoid of σ -targeting. [Mh] Termos MeSH primário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores Antineoplásicos/farmacologia Quelantes/farmacologia Neoplasias Pancreáticas/tratamento farmacológico Receptores sigma/antagonistas & inibidores Tiossemicarbazonas/farmacologia [Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo Animais Antineoplásicos/síntese química Antineoplásicos/química Morte Celular/efeitos dos fármacos Proliferação Celular/efeitos dos fármacos Sobrevivência Celular/efeitos dos fármacos Quelantes/síntese química Quelantes/química Modelos Animais de Doenças Relação Dose-Resposta a Droga Ensaios de Seleção de Medicamentos Antitumorais Feminino Seres Humanos Camundongos Camundongos Endogâmicos C57BL Estrutura Molecular Neoplasias Experimentais/tratamento farmacológico Neoplasias Experimentais/metabolismo Neoplasias Experimentais/patologia Neoplasias Pancreáticas/metabolismo Neoplasias Pancreáticas/patologia Receptores sigma/metabolismo Relação Estrutura-Atividade Tiossemicarbazonas/síntese química Tiossemicarbazonas/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Antineoplastic Agents); 0 (Chelating Agents); 0 (Receptors, sigma); 0 (Thiosemicarbazones); 0 (sigma-2 receptor) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180223 [Lr] Data última revisão: 180223 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171230 [St] Status: MEDLINE

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[PMID]: 29172528 [Au] Autor: Amata E; Dichiara M; Arena E; Pittalà V; Pistarà V; Cardile V; Graziano ACE; Fraix A; Marrazzo A; Sortino S; Prezzavento O [Ad] Endereço: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania , Viale A. Doria 6, 95125 Catania, Italy. [Ti] Título: Novel Sigma Receptor Ligand-Nitric Oxide Photodonors: Molecular Hybrids for Double-Targeted Antiproliferative Effect. [So] Source: J Med Chem;60(23):9531-9544, 2017 Dec 14. [Is] ISSN: 1520-4804 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: This contribution reports the synthesis and evaluation of novel hybrid compounds that conjugate a sigma (σ) receptor pharmacophore and a nitric oxide (NO) photodonor. All compounds preserve their capability to generate NO under visible light and possess overall σ receptor nanomolar affinity, with one of them (8b) exhibiting remarkable σ receptor selectivity. Compounds 8b, 11a, and 11b were tested on tumorigenic MCF-7 and A2058 cells expressing high levels of σ and σ receptor, respectively. Considerable loss of cell viability was detected under light excitation, while negligible effects in the dark were detected. Moreover, they did not show any significant cytotoxicity in the dark or under irradiation on nontumorigenic NCTC-2544 keratinocytes. NO-induced reduction of cellular viability was demonstrated by in-cell NO detection and total nitrite estimation. For the first time, a combination of σ receptor moieties and a NO photodonor is reported, providing distinctive ligands potentially useful for cancer management. [Mh] Termos MeSH primário: Antineoplásicos/química Antineoplásicos/farmacologia Proliferação Celular/efeitos dos fármacos Neoplasias/tratamento farmacológico Doadores de Óxido Nítrico/química Doadores de Óxido Nítrico/farmacologia Receptores sigma/metabolismo [Mh] Termos MeSH secundário: Linhagem Celular Sobrevivência Celular/efeitos dos fármacos Seres Humanos Luz Células MCF-7 Neoplasias/metabolismo Óxido Nítrico/metabolismo Fotoquimioterapia Fármacos Fotossensibilizantes/química Fármacos Fotossensibilizantes/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Nitric Oxide Donors); 0 (Photosensitizing Agents); 0 (Receptors, sigma); 31C4KY9ESH (Nitric Oxide) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171229 [Lr] Data última revisão: 171229 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171128 [St] Status: MEDLINE [do] DOI: 10.1021/acs.jmedchem.7b00791

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[PMID]: 28898265 [Au] Autor: Zhao J; Mysona BA; Wang J; Gonsalvez GB; Smith SB; Bollinger KE [Ad] Endereço: James and Jean Culver Vision Discovery Institute, Augusta, Georgia, United States of America. [Ti] Título: Sigma 1 receptor regulates ERK activation and promotes survival of optic nerve head astrocytes. [So] Source: PLoS One;12(9):e0184421, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The sigma 1 receptor (S1R) is a unique transmembrane protein that has been shown to regulate neuronal differentiation and cellular survival. It is expressed within several cell types throughout the nervous system and visceral organs, including neurons and glia within the eye. S1R ligands are therapeutic targets for diseases ranging from neurodegenerative conditions to neoplastic disorders. However, effects of S1R activation and inhibition within glia cells are not well characterized. Within the eye, the astrocytes at the optic nerve head are crucial to the health and survival of the neurons that send visual information to the brain. In this study, we used the S1R-specific agonist, (+)-pentazocine, to evaluate S1R activation within optic nerve head-derived astrocytes (ONHAs). Treatment of ONHAs with (+)-pentazocine attenuated the level and duration of stress-induced ERK phosphorylation following oxidative stress exposure and promoted survival of ONHAs. These effects were specific to S1R activation because they were not observed in ONHAs that were depleted of S1R using siRNA-mediated knockdown. Collectively, our results suggest that S1R activation suppresses ERK1/2 phosphorylation and protects ONHAs from oxidative stress-induced death. [Mh] Termos MeSH primário: Astrócitos/metabolismo Nervo Óptico/metabolismo Receptores sigma/metabolismo [Mh] Termos MeSH secundário: Analgésicos Opioides/farmacologia Animais Astrócitos/efeitos dos fármacos Células Cultivadas Células HeLa Seres Humanos Proteína Quinase 1 Ativada por Mitógeno/metabolismo Proteína Quinase 3 Ativada por Mitógeno/metabolismo Nervo Óptico/citologia Estresse Oxidativo Pentazocina/farmacologia Ratos Ratos Sprague-Dawley Receptores sigma/agonistas [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Analgesics, Opioid); 0 (Receptors, sigma); 0 (sigma-1 receptor); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3); RP4A60D26L (Pentazocine) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171012 [Lr] Data última revisão: 171012 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170913 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0184421

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[PMID]: 28877319 [Au] Autor: Wang J; Saul A; Cui X; Roon P; Smith SB [Ad] Endereço: Department of Cellular Biology and Anatomy, The Medical College of Georgia at Augusta University, Augusta, Georgia, United States. [Ti] Título: Absence of Sigma 1 Receptor Accelerates Photoreceptor Cell Death in a Murine Model of Retinitis Pigmentosa. [So] Source: Invest Ophthalmol Vis Sci;58(11):4545-4558, 2017 Sep 01. [Is] ISSN: 1552-5783 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Purpose: Sigma 1 Receptor (Sig1R) is a novel therapeutic target in neurodegenerative diseases, including retinal disease. Sig1R-/- mice have late-onset retinal degeneration with ganglion cell loss that worsens under stress. Whether Sig1R plays a role in maintaining other retinal neurons is unknown, but was investigated here using rd10 mice, a model of severe photoreceptor degeneration. Methods: Wild-type, rd10, and rd10/Sig1R-/- mice were subjected to ERG and spectral-domain optical coherence tomography (SD-OCT) to assess visual function/structure in situ. Retinas imaged microscopically were subjected to morphometric analysis, immunodetection of cones, and analysis of gliosis. Oxidative and endoplasmic reticulum (ER) stress was evaluated at mRNA/protein levels. Results: Photopic ERG responses were reduced significantly in rd10/Sig1R-/- versus rd10 mice at P28 (31 ± 6 vs. 56 ± 7 µV), indicating accelerated cone loss when Sig1R was absent. At P28, SD-OCT revealed reduced retinal thickness in rd10/Sig1R-/- mice (60% of WT) versus rd10 (80% of WT). Morphometric analysis disclosed profound photoreceptor nuclei loss in rd10/Sig1R-/- versus rd10 mice. rd10/Sig1R-/- mice had 35% and 60% fewer photoreceptors, respectively, at P28 and P35, than rd10. Peanut agglutinin cone labeling decreased significantly; gliosis increased significantly in rd10/Sig1R-/- versus rd10 mice. At P21, NRF2 levels increased in rd10/Sig1R-/- mice versus rd10 and downstream antioxidants increased indicating oxidative stress. At P28, ER stress genes/proteins, especially XBP1, a potent transcriptional activator of the unfolded protein response and CHOP, a proapoptotic transcription factor, increased significantly in rd10/Sig1R-/- mice versus rd10. Conclusions: Photoreceptor cell degeneration accelerates and cone function diminishes much earlier in rd10/Sig1R-/- than rd10 mice emphasizing the importance of Sig1R as a modulator of retinal cell survival. [Mh] Termos MeSH primário: Apoptose Modelos Animais de Doenças Receptores sigma/fisiologia Células Fotorreceptoras Retinianas Cones/patologia Células Fotorreceptoras Retinianas Bastonetes/patologia Retinite Pigmentosa/patologia [Mh] Termos MeSH secundário: Animais Eletrorretinografia Feminino Técnica Indireta de Fluorescência para Anticorpo Masculino Camundongos Camundongos Endogâmicos C57BL Camundongos Knockout Estresse Oxidativo Retina/fisiologia Tomografia de Coerência Óptica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Receptors, sigma); 0 (sigma-1 receptor) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170919 [Lr] Data última revisão: 170919 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170907 [St] Status: MEDLINE [do] DOI: 10.1167/iovs.17-21947

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[PMID]: 28869398 [Au] Autor: Dichiara M; Amata E; Rescifina A; Prezzavento O; Floresta G; Parenti C; Pittalà V; Marrazzo A [Ad] Endereço: Dipartimento di Scienze del Farmaco, Università di Catania, Viale Andrea Doria 6, 95125 Catania, Italy. [Ti] Título: Synthesis and evaluation of haloperidol metabolite II prodrugs as anticancer agents. [So] Source: Future Med Chem;9(15):1749-1764, 2017 Oct. [Is] ISSN: 1756-8927 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The use of haloperidol metabolite II (HP-metabolite II) prodrugs is an emerging strategy in the treatment of cancer. HP-metabolite II exhibits antiproliferative properties at micromolar concentrations inducing apoptosis in different types of cancer. Thus, the application of the prodrug approach appears as a useful method leading to much more desirable pharmacokinetic and pharmacodynamic properties. Some studies have shown that the esterification of the hydroxyl group of HP-metabolite II with 4-phenylbutiric acid (4-PBA) or valproic acid enhances the anticancer therapeutic potency. The current progresses in the design, synthesis and evaluation of anticancer activity of HP metabolite II prodrugs will be discussed in this review. [Mh] Termos MeSH primário: Haloperidol/farmacologia Pró-Fármacos/síntese química Pró-Fármacos/farmacologia [Mh] Termos MeSH secundário: Antineoplásicos/síntese química Antineoplásicos/farmacologia Sobrevivência Celular/efeitos dos fármacos Haloperidol/química Haloperidol/metabolismo Inibidores de Histona Desacetilases/síntese química Inibidores de Histona Desacetilases/química Inibidores de Histona Desacetilases/farmacologia Seres Humanos Fenilbutiratos/química Fenilbutiratos/farmacologia Receptores sigma/antagonistas & inibidores Receptores sigma/metabolismo Transdução de Sinais/efeitos dos fármacos Ácido Valproico/química Ácido Valproico/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Histone Deacetylase Inhibitors); 0 (Phenylbutyrates); 0 (Prodrugs); 0 (Receptors, sigma); 614OI1Z5WI (Valproic Acid); J6292F8L3D (Haloperidol) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171025 [Lr] Data última revisão: 171025 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170905 [St] Status: MEDLINE [do] DOI: 10.4155/fmc-2017-0064

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[PMID]: 28866257 [Au] Autor: Floresta G; Rescifina A; Marrazzo A; Dichiara M; Pistarà V; Pittalà V; Prezzavento O; Amata E [Ad] Endereço: Department of Drug Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy; Department of Chemical Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy. [Ti] Título: Hyphenated 3D-QSAR statistical model-scaffold hopping analysis for the identification of potentially potent and selective sigma-2 receptor ligands. [So] Source: Eur J Med Chem;139:884-891, 2017 Oct 20. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: A 3D quantitative structure-activity relationship (3D-QSAR) model for predicting the σ receptor affinity has been constructed with the aim of providing a useful tool for the identification, design, and optimization of novel σ receptor ligands. The model has been built using a set of 500 selective σ receptor ligands recovered from the sigma-2 receptor selective ligand database (S2RSLDB) and developed with the software Forge. The present model showed high statistical quality as confirmed by its robust predictive potential and satisfactory descriptive capability. The drawn up 3D map allows for a prompt visual comprehension of the electrostatic, hydrophobic, and shaping features underlying σ receptor ligands interaction. A theoretic approach for the generation of new lead compounds with optimized σ receptor affinity has been performed by means of scaffold hopping analysis. Obtained results further confirmed the validity of our model being some of the identified moieties have already been successfully employed in the development of potent σ receptor ligands. For the first time is herein reported a 3D-QSAR model which includes a number of chemically diverse σ receptor ligands and well accounts for the individual ligands affinities. These features will ensure prospectively advantageous applications to speed up the identification of new potent and selective σ receptor ligands. [Mh] Termos MeSH primário: Relação Quantitativa Estrutura-Atividade Receptores sigma/antagonistas & inibidores [Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga Seres Humanos Ligantes Modelos Moleculares Estrutura Molecular [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Ligands); 0 (Receptors, sigma); 0 (sigma-2 receptor) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171016 [Lr] Data última revisão: 171016 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170904 [St] Status: MEDLINE

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[PMID]: 28815595 [Au] Autor: Brindley RL; Bauer MB; Hartley ND; Horning KJ; Currie KPM [Ad] Endereço: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. [Ti] Título: Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors. [So] Source: J Neurochem;143(2):171-182, 2017 Oct. [Is] ISSN: 1471-4159 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT receptors to control secretion. In addition to blocking the serotonin transporter, some selective serotonin reuptake inhibitors (SSRIs) are also agonists at sigma-1 receptors which function as intracellular chaperone proteins and can translocate to the plasma membrane to modulate ion channels. Therefore, we investigated whether SSRIs and other sigma-1 receptor ligands can modulate stimulus-secretion coupling in ACCs. Escitalopram and fluvoxamine (100 nM to 1 µM) reversibly inhibited nAChR currents. The sigma-1 receptor antagonists NE-100 and BD-1047 also blocked nAChR currents (≈ 50% block at 100 nM) as did PRE-084, a sigma-1 receptor agonist. Block of nAChR currents by fluvoxamine and NE-100 was not additive suggesting a common site of action. VGCC currents were unaffected by the drugs. Neither the increase in cytosolic [Ca ] nor the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs was altered by fluvoxamine or NE-100. However, both Ca entry and catecholamine secretion evoked by the cholinergic agonist carbachol were significantly reduced by fluvoxamine or NE-100. Together, our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, SSRIs and other sigma-1 receptor ligands inhibit secretion evoked by cholinergic stimulation because of direct block of Ca entry via nAChRs. [Mh] Termos MeSH primário: Medula Suprarrenal/secreção Catecolaminas/secreção Células Cromafins/secreção Antagonistas Nicotínicos/farmacologia Receptores Nicotínicos/fisiologia Receptores sigma/fisiologia [Mh] Termos MeSH secundário: Medula Suprarrenal/citologia Medula Suprarrenal/efeitos dos fármacos Animais Anisóis/farmacologia Catecolaminas/antagonistas & inibidores Bovinos Células Cultivadas Células Cromafins/efeitos dos fármacos Relação Dose-Resposta a Droga Ligantes Masculino Camundongos Camundongos Endogâmicos C57BL Propilaminas/farmacologia Receptores sigma/agonistas [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anisoles); 0 (Catecholamines); 0 (Ligands); 0 (Nicotinic Antagonists); 0 (Propylamines); 0 (Receptors, Nicotinic); 0 (Receptors, sigma); 0 (sigma-1 receptor); 149409-57-4 (N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171012 [Lr] Data última revisão: 171012 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170818 [St] Status: MEDLINE [do] DOI: 10.1111/jnc.14149

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[PMID]: 28764962 [Au] Autor: Fanter L; Müller C; Schepmann D; Bracher F; Wünsch B [Ad] Endereço: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany. [Ti] Título: Chiral-pool synthesis of 1,2,4-trisubstituted 1,4-diazepanes as novel σ receptor ligands. [So] Source: Bioorg Med Chem;25(17):4778-4799, 2017 Sep 01. [Is] ISSN: 1464-3391 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Starting from enantiomerically pure amino acids, 1,4-diazepanes with various substituents in 1, 2, and 4-position were synthesized following the late stage diversification strategy. The key step in the formation of the seven-membered ring was the intramolecular EDC coupling of amino acids 15, 26, and 39. The configuration in 2-position does not influence the σ affinity and selectivity over related receptors. A cyclohexylmethyl or a butyl group are the preferred substituents in 4-position, whereas a methyl moiety in 2-position and a (substituted) benzyl moiety in 1-position result in the highest σ affinity. These results fit nicely to the reported σ pharmacophore models. The compounds did not inhibit the structurally related fungal enzyme sterol Δ -isomerase, but showed inhibition of diverse enzymes in late cholesterol biosynthesis at high concentrations. In a screening against more than 50 target proteins, (2S)-1-benzyl-4-(4-methoxybenzyl)-2-methyl-1,4-diazepane ((S)-28b, K (σ )=0.86nM) showed a clean receptor profile. The dose dependent potentiation of electrically stimulated contractions of guinea pig vas deferens indicates σ agonistic activity of (S)-28b. Even at a dose of 100mg/kg (S)-28b did not induce severe toxic or behavioral effects in the Irwin screen. Clear cognition enhancing effects were observed for (S)-28b after inducing amnesia by scopolamine. [Mh] Termos MeSH primário: Azepinas/metabolismo Receptores sigma/metabolismo [Mh] Termos MeSH secundário: Animais Azepinas/química Azepinas/farmacologia Azepinas/toxicidade Colesterol/biossíntese Ativação Enzimática/efeitos dos fármacos Inibidores Enzimáticos/síntese química Inibidores Enzimáticos/metabolismo Inibidores Enzimáticos/farmacologia Inibidores Enzimáticos/toxicidade Cobaias Cinética Ligantes Masculino Contração Muscular/efeitos dos fármacos Ligação Proteica Receptores sigma/agonistas Estereoisomerismo Relação Estrutura-Atividade Leveduras/efeitos dos fármacos Leveduras/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (1,4-diazepane); 0 (Azepines); 0 (Enzyme Inhibitors); 0 (Ligands); 0 (Receptors, sigma); 97C5T2UQ7J (Cholesterol) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170926 [Lr] Data última revisão: 170926 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170803 [St] Status: MEDLINE

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[PMID]: 28756263 [Au] Autor: Donnier-Maréchal M; Carato P; Larchanché PE; Ravez S; Boulahjar R; Barczyk A; Oxombre B; Vermersch P; Melnyk P [Ad] Endereço: Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000 Lille, France. Electronic address: md781@cam.ac.uk. [Ti] Título: Synthesis and pharmacological evaluation of benzamide derivatives as potent and selective sigma-1 protein ligands. [So] Source: Eur J Med Chem;138:964-978, 2017 Sep 29. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: A series of novel benzamide-derived compounds was designed, synthesized and pharmacologically evaluated. Among all 37 synthesized compounds, two series were developed with the modulation of the nature, the position of atoms or groups on the benzamide scaffold, but also the nature of the amine group separated from the benzamide with 2, 3 or 4 methylene groups. In vitro competition binding assays against sigma proteins (sigma-1 S1R and sigma-2 S2R) revealed that most of them conferred S2R/S1R selectivity toward without cytotoxic effects on SY5Y cells, especially with the first series with compounds 7a-z. Some selected compounds were also evaluated for their agonist and antagonist activities on a panel of 40 receptors. Results showed the importance of the nature and the position with halogeno atom on the benzamide scaffold, the length chain but also the contribution of the hydrophobic part on the amine group. Among them, compounds 7i, w, y with Cl, CN or NO groups at the 4-position of the benzamide scaffold showed excellent affinity for S1R (Ki = 1.2-3.6 nM), selectivity for S2R (Ki up to 1400 nM) and high selectivity index (IC /Ki ratio from 28 000 to 83 000). Futhermore, these compounds presented an excellent safety profile over 40 other receptors. These derivatives will be selected for further biological investigations. [Mh] Termos MeSH primário: Benzamidas/farmacologia Receptores sigma/agonistas Receptores sigma/antagonistas & inibidores [Mh] Termos MeSH secundário: Benzamidas/síntese química Benzamidas/química Linhagem Celular Tumoral Relação Dose-Resposta a Droga Seres Humanos Ligantes Estrutura Molecular Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Benzamides); 0 (Ligands); 0 (Receptors, sigma); 6X80438640 (benzamide) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170929 [Lr] Data última revisão: 170929 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170731 [St] Status: MEDLINE

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[PMID]: 28756230 [Au] Autor: Bai T; Wang S; Zhao Y; Zhu R; Wang W; Sun Y [Ad] Endereço: Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, School of Medicine, Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, PR China. [Ti] Título: Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells. [So] Source: Biochem Biophys Res Commun;491(4):919-925, 2017 Sep 30. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Ferroptosis is a novel form of cell death, which is characterized by accumulation of reactive oxygen species (ROS). Sigma 1 receptor (S1R) has been suggested to function in oxidative stress metabolism. Both erastin and sorafenib significantly induced S1R protein expression. Haloperidol strongly promoted erastin- and sorafenib-induced cell death, which was blocked by ferrostatin-1 but not ZVAD-FMK or necrosulfonamide. During ferroptosis, haloperidol substantially increased the cellular levels of Fe , GSH and lipid peroxidation. Furthermore, several ferroptosis-related protein targets were up-regulated in the absence of haloperidol. Thus, Our study identified an association between haloperidol and ferroptosis for the first time. Our analyses of a combination of drugs may provide a novel strategy of hepatocellular carcinoma (HCC) therapy. [Mh] Termos MeSH primário: Carcinoma Hepatocelular/tratamento farmacológico Carcinoma Hepatocelular/patologia Haloperidol/farmacologia Ferro/metabolismo Neoplasias Hepáticas/tratamento farmacológico Neoplasias Hepáticas/patologia Receptores sigma/antagonistas & inibidores [Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos Sobrevivência Celular/efeitos dos fármacos Relação Dose-Resposta a Droga Seres Humanos Niacinamida/análogos & derivados Niacinamida/farmacologia Compostos de Fenilureia/farmacologia Piperazinas/farmacologia Receptores sigma/genética Receptores sigma/metabolismo Relação Estrutura-Atividade Células Tumorais Cultivadas [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Phenylurea Compounds); 0 (Piperazines); 0 (Receptors, sigma); 0 (erastin); 0 (sigma-1 receptor); 25X51I8RD4 (Niacinamide); 9ZOQ3TZI87 (sorafenib); E1UOL152H7 (Iron); J6292F8L3D (Haloperidol) [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: 170731 [St] Status: MEDLINE

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