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1.
Molecules ; 27(1)2021 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-35011448

RESUMO

This study focused on developing Panos nanoemulsion (P-NE) and enhancing the anti-inflammatory efficacy for the treatment of inflammation. The effects of P-NE were evaluated in terms of Nitric oxide (NO production) in Lipopolysaccharide (LPS), induced RAW 264.7 cells, Reactive oxygen species (ROS) generation using Human Keratinocyte cells (HaCaT), and quantitative polymerase chain reaction (qPCR) analysis. Sea buckthorn oil, Tween 80, and span 80 were used and optimize the process. Panos extract (P-Ext) was prepared using the fermentation process. Further high-energy ultra-sonication was used for the preparation of P-NE. The developed nanoemulsion (NE) was characterized using different analytical methods. Field emission transmission electron microscopy (FE-TEM) analyzed the spherical shape and morphology. In addition, stability was analyzed by Dynamic light scattering (DLS) analysis, where particle size was analyzed 83 nm, and Zeta potential -28.20 ± 2 (mV). Furthermore, 90 days of stability was tested using different temperatures conditions where excellent stability was observed. P-NE are non-toxic in (HaCaT), and RAW264.7 cells up to 100 µg/mL further showed effects on ROS and NO production of the cells at 50 µg/mL. The qPCR analysis demonstrated the suppression of pro-inflammatory mediators for (Cox 2, IL-6, IL-1ß, and TNF-α, NF-κB, Ikkα, and iNOS) gene expression. The prepared NE exhibited anti-inflammatory effects, demonstrating its potential as a safe and non-toxic nanomedicine.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Emulsões , Fermentação , Extratos Vegetais/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Fenômenos Químicos , Estabilidade de Medicamentos , Mediadores da Inflamação , Camundongos , Óxido Nítrico/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Análise Espectral
2.
Mol Cancer Ther ; 19(8): 1649-1659, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32404408

RESUMO

Multiple myeloma is a hematologic cancer that disrupts normal bone marrow function and has multiple lines of therapeutic options, but is incurable as patients ultimately relapse. We developed a novel antibody-drug conjugate (ADC) targeting CS-1, a protein that is highly expressed on multiple myeloma tumor cells. The anti-CS-1 mAb specifically bound to cells expressing CS-1 and, when conjugated to a cytotoxic pyrrolobenzodiazepine payload, reduced the viability of multiple myeloma cell lines in vitro In mouse models of multiple myeloma, a single administration of the CS-1 ADC caused durable regressions in disseminated models and complete regression in a subcutaneous model. In an exploratory study in cynomolgus monkeys, the CS-1 ADC demonstrated a half-life of 3 to 6 days; however, no highest nonseverely toxic dose was achieved, as bone marrow toxicity was dose limiting. Bone marrow from dosed monkeys showed reductions in progenitor cells as compared with normal marrow. In vitro cell killing assays demonstrated that the CS-1 ADC substantially reduced the number of progenitor cells in healthy bone marrow, leading us to identify previously unreported CS-1 expression on a small population of progenitor cells in the myeloid-erythroid lineage. This finding suggests that bone marrow toxicity is the result of both on-target and off-target killing by the ADC.


Assuntos
Anticorpos Monoclonais/química , Antineoplásicos/farmacologia , Benzodiazepinas/química , Imunoconjugados/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas dos Microfilamentos/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Pirróis/química , Animais , Antineoplásicos/química , Apoptose , Proliferação de Células , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Imunoconjugados/química , Macaca fascicularis , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas dos Microfilamentos/imunologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Photochem Photobiol B ; 199: 111588, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31450132

RESUMO

Green synthesis of zinc oxide has gained extensive attention as a reliable, sustainable, and eco-friendly protocol to reduce the destructive effects associated with the traditional synthesis methods commonly utilized in laboratory and industry. Here for the first time, we have synthesized quaker ladies flower type ZnO (ZnO/QNF) from panos extract (extract from four panax plants such as Panax ginseng, Acanthopanax senticosus, Kalopanax septemlobus and Dendropanax morbifera). The synthesized ZnO materials was characterized using powder X-ray diffraction, Fourier infrared spectroscopy, X-ray photoelectron spectroscopy and Transmission electron microscope. The newly synthesized ZnO/QNF was applied for the removal of industrial dyes such as methylene blue (MB), Eosin Y (EY) and Malachite green (MG) under UV illumination. The photocatalyst degraded the 15 mg L-1 MB, EY and MG to >99% within 80, 90 and 110 min of contact time, respectively. In addition, the ZnO/QNF photocatalyst removed the low concentrated 5 mg L-1 of MB, EY, and MG within 30, 35 and 40 min of contact time, respectively. The pedal structure provided all the active sites available for the easy interaction with dye molecule under UV, and that enabled fast kinetics of dye degradation than the many other benchmark materials reported previously. The ZnO photocatalyst could be reused minimum of five cycles without any significant loss in degradation efficiency.


Assuntos
Benzodiazepinas/química , Corantes/química , Nanoestruturas/química , Extratos Vegetais/química , Óxido de Zinco/química , Catálise , Amarelo de Eosina-(YS)/química , Química Verde/métodos , Cinética , Azul de Metileno/química , Processos Fotoquímicos , Corantes de Rosanilina/química , Raios Ultravioleta
4.
Int J Biol Macromol ; 110: 269-275, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29402457

RESUMO

Olanzapine is an atypical antipsychotic, undergoes extensive first pass metabolism, also has poor aqueous solubility and belongs to BCS (Biopharmaceutical Classification System) Class II drug) exhibit low oral bioavailability. To overcome this and to enhance the bioavailability, intestinal lymphatic transport of drugs can be exploited through Nano structured lipid carriers (NLCs). The NLCs were formulated by solvent diffusion method using solid lipid (glyceryl tripalmitate), liquid lipid (castor oil) and surfactants (Pluronic F-68, Soylecithin). The formulated NLCs were characterized for physico-chemical properties, in-vitro release studies and in-vivo oral bioavailability. F6 has shown average particle size of 158.5 nm with PI of 0.115 indicating narrow particle size distribution and follows uni modal distribution. It was found that the batch with stearyl amine has a zeta potential of 28.39 mV which confers stability to the dispersion. Bioavailability studies indicate that there was more than 5½-fold increase in oral bioavailability in case of NLCs (F6) compared to olanzapine suspension which indicates that NLCs provided sustained release of the drugs, and these systems can be the preferred as drug carriers for lipophilic drugs in long term disease conditions such as schizophrenia for enhanced bioavailability.


Assuntos
Antipsicóticos , Benzodiazepinas , Portadores de Fármacos , Nanopartículas , Administração Oral , Animais , Antipsicóticos/química , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacocinética , Benzodiazepinas/farmacologia , Disponibilidade Biológica , Óleo de Rícino/química , Óleo de Rícino/farmacocinética , Óleo de Rícino/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Lecitinas/química , Lecitinas/farmacocinética , Lecitinas/farmacologia , Masculino , Nanopartículas/química , Nanopartículas/uso terapêutico , Olanzapina , Poloxâmero/química , Poloxâmero/farmacocinética , Poloxâmero/farmacologia , Ratos , Ratos Wistar , Triglicerídeos/química , Triglicerídeos/farmacocinética , Triglicerídeos/farmacologia
5.
ACS Chem Neurosci ; 9(10): 2307-2330, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29342356

RESUMO

Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.


Assuntos
Estimulantes do Sistema Nervoso Central/síntese química , Alucinógenos/síntese química , Alcaloides Opiáceos/síntese química , Psicotrópicos/síntese química , Anfetaminas/síntese química , Anfetaminas/química , Anfetaminas/história , Benzodiazepinas/síntese química , Benzodiazepinas/química , Benzodiazepinas/história , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/história , Cocaína/síntese química , Cocaína/química , Cocaína/história , Cocaína Crack/síntese química , Cocaína Crack/química , Cocaína Crack/história , Indústria Farmacêutica , Overdose de Drogas/epidemiologia , Tolerância a Medicamentos , Epidemias , Alucinógenos/química , Alucinógenos/história , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , Humanos , N-Metil-3,4-Metilenodioxianfetamina/síntese química , N-Metil-3,4-Metilenodioxianfetamina/química , N-Metil-3,4-Metilenodioxianfetamina/história , Alcaloides Opiáceos/química , Alcaloides Opiáceos/história , Ópio/história , Oxicodona/síntese química , Oxicodona/química , Oxicodona/história , Psicotrópicos/química , Psicotrópicos/história , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Medicamentos Sintéticos/síntese química , Medicamentos Sintéticos/química , Medicamentos Sintéticos/história , Estados Unidos/epidemiologia
6.
J Biol Regul Homeost Agents ; 31(3): 683-689, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28956418

RESUMO

Smyrnium cordifolium as a wild plant is used in traditional medicine in Iran for the treatment of anxiety and insomnia. The anticonvulsant effect of this plant has not been studied to date, therefore this study aimed to evaluate the anticonvulsant effects of its essential oil and curzerene on seizure. Essential oil of the Smyrnium cordifolium plant was prepared by the hydro-distillation method. Gas chromatography and gas chromatography-mass spectroscopy analysis of the essential oil revealed its main components. Anticonvulsant effects of Smyrnium cordifolium essential oil (SCEO) and curzerene were examined on mice using the pentylentetrazole model (PTZ). Flumazenil (2 mg/kg, i.p) and naloxone (5 mg/kg, i.p) were injected into the relevant groups of mice to realize the anticonvulsant mechanism of SCEO and curzerene, respectively. The main identified components of the plant were curzerene (65.26%), δ-Cadinene (14.39%) and γ-elemene (5.15%), which comprised approximately 85.28% of SCEO. The ED50 values of SCEO and curzerene in the PTZ model were 223±15 and 0.25±0.09 mg/kg, respectively. Curzerene at the dosage of 0.4 mg/kg prolonged the onset time of seizure and decreased the duration of seizure among treated group compared to the saline group. At the dosage of 0.4 mg/kg, seizure and mortality protection rates for the treated group were 100%. Flumazenil and naloxone could suppress the anticonvulsant effects of SCEO and curzerene. It seems that SCEO and curzerene are useful for the treatment of absence seizure and this effect may be related to their effects on GABAergic and opioid systems.


Assuntos
Apiaceae/química , Benzodiazepinas/farmacologia , Antagonistas de Entorpecentes/farmacologia , Óleos Voláteis/farmacologia , Pentilenotetrazol/efeitos adversos , Convulsões , Animais , Benzodiazepinas/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Antagonistas de Entorpecentes/química , Óleos Voláteis/química , Pentilenotetrazol/farmacologia , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia
7.
ACS Chem Neurosci ; 8(7): 1543-1553, 2017 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-28375612

RESUMO

Neuroleptic drugs are widely applied in effective treatment of schizophrenia and related disorders. The lipophilic character of neuroleptics means that they tend to accumulate in the lipid membranes, impacting their functioning and processing. In this paper, the effect of four drugs, namely, thioridazine, olanzapine, sulpiride, and amisulpride, on neutral and negatively charged lipid bilayers was examined. The interaction of neuroleptics with lipids and the subsequent changes in the membrane physical properties was assessed using several complementary biophysical approaches (isothermal titration calorimetry, electron paramagnetic resonance spectroscopy, dynamic light scattering, and ζ potential measurements). We have determined the thermodynamic parameters, that is, the enthalpy of interaction and the binding constant, to describe the interactions of the investigated drugs with model membranes. Unlike thioridazine and olanzapine, which bind to both neutral and negatively charged membranes, amisulpride interacts with only the negatively charged one, while sulpiride does not bind to any of them. The mechanism of olanzapine and thioridazine insertion into the bilayer membrane cannot be described merely by a simple molecule partition between two different phases (the aqueous and the lipid phase). We have estimated the number of protons transferred in the course of drug binding to determine which of its forms, ionized or neutral, binds more strongly to the membrane. Finally, electron paramagnetic resonance results indicated that the drugs are localized near the water-membrane interface of the bilayer and presence of a negative charge promotes their burying deeper into the membrane.


Assuntos
Antipsicóticos/química , Benzodiazepinas/química , Membranas Artificiais , Sulpirida/análogos & derivados , Sulpirida/química , Tioridazina/química , Amissulprida , Antipsicóticos/farmacologia , Benzodiazepinas/farmacologia , Calorimetria , Difusão Dinâmica da Luz , Espectroscopia de Ressonância de Spin Eletrônica , Modelos Químicos , Estrutura Molecular , Olanzapina , Fosfatidilcolinas/química , Fosfatidilgliceróis/química , Prótons , Sulpirida/farmacologia , Termodinâmica , Tioridazina/farmacologia , Água/química
8.
Pharmacol Biochem Behav ; 157: 35-40, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28442369

RESUMO

Positive allosteric modulators of GABAA receptors transduce a host of beneficial effects including anxiolytic actions. We have recently shown that bioavailability and anxiolytic-like activity can be improved by eliminating the ester functionality in imidazo[1,5-a][1,4]diazepines. In the present series of experiments, we further substantiate the value of heterocyle replacement of the ester for potential treatment of anxiety. None of three esters was active in a Vogel conflict test in rats that detects anxiolytic drugs like diazepam. Compounds 7 and 8, ester bioisosters, were selective for alpha 2 and 3 over alpha 1-containing GABAA receptors but also had modest efficacy at GABAA alpha 5-containing receptors. Compound 7 was efficacious and potent in this anxiolytic-detecting assay without affecting non-punished responding. The efficacies of the esters and of compound 7 were predicted from their efficacies as anticonvulsants against the GABAA antagonist pentylenetetrazole (PTZ). In contrast, the related structural analog, compound 8, did not produce anxiolytic-like effects in rats despite anticonvulsant efficacy. These data thus support the following conclusions: 1) ancillary pharmacological actions of compound 8 might be responsible for its lack of anxiolytic-like efficacy despite its efficacy as an anticonvulsant 2) esters of imidazo[1,5-a][1,4]diazepines do not demonstrate anxiolytic-like effects in rats due to their low bioavailability and 3) replacement of the ester function with suitable heterocycles markedly improves bioavailability and engenders molecules with the opportunity to have potent and efficacious effects in vivo that correspond to human anxiolytic actions.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Benzodiazepinas/uso terapêutico , Agonistas de Receptores de GABA-A/uso terapêutico , Receptores de GABA-A/fisiologia , Animais , Ansiolíticos/química , Ansiedade/psicologia , Benzodiazepinas/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Agonistas de Receptores de GABA-A/química , Células HEK293 , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
9.
Bioorg Med Chem Lett ; 27(5): 1154-1158, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28188066

RESUMO

A novel pyrrolobenzodiazepine dimer payload, SG3227, was rationally designed based on the naturally occurring antitumour compound sibiromycin. SG3227 was synthesized from a dimeric core in an efficient fashion. An unexpected room temperature Diels-Alder reaction occurred during the final step of the synthesis and was circumvented by use of an iodoacetamide conjugation moiety in place of a maleimide. The payload was successfully conjugated to trastuzumab and the resulting ADC exhibited potent activity against a HER2-expressing human cancer cell line in vitro.


Assuntos
Aminoglicosídeos/química , Antineoplásicos/química , Benzodiazepinas/química , Imunoconjugados/química , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro
10.
Colloids Surf B Biointerfaces ; 152: 289-295, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28126680

RESUMO

Atypical antipsychotic drugs induce hepatic toxicity. Thus, it is of importance to eliminate the side effects of these drugs. Herein we describe the preparation of nanoemulsions with a dietary supplement; wheat germ oil (WGO), to ameliorate the liver damage induced by clozapine and olanzapine. THLE-2 cell line was used as a model to investigate the effects of these nanoemulsions on cell viability as well as antioxidative efficiency after antipsychotic insult. In this context, a conventional cell culture method; MTT was used along with a novel cellular imaging technique called digital holography (DH) to evaluate cell viability. Obtained data confirmed that both clozapine and olanzapine induced the liver damage in in vitro model and WGO nanoemulsions were found to be effective on cells and eliminate the cytotoxic effects of these drugs. Briefly, this study has some outputs as follows; it showed that different dietary supplements can be used in such formulations instead of their pristine forms to increase bioavailability. Also, DH was successfully applied for the monitoring of cell viability and it could be a promising approach as the reactive-free cytotoxicity test.


Assuntos
Antipsicóticos/efeitos adversos , Emulsões/química , Holografia/métodos , Nanopartículas/química , Antipsicóticos/química , Benzodiazepinas/efeitos adversos , Benzodiazepinas/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Clozapina/efeitos adversos , Clozapina/química , Suplementos Nutricionais , Humanos , Nanopartículas/efeitos adversos , Olanzapina , Óleos de Plantas/química , Óleos de Plantas/farmacologia
11.
Eur J Med Chem ; 126: 550-560, 2017 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-27915170

RESUMO

We describe the synthesis of analogs of XHE-III-74, a selective α4ß3γ2 GABAAR ligand, shown to relax airway smooth muscle ex vivo and reduce airway hyperresponsiveness in a murine asthma model. To improve properties of this compound as an asthma therapeutic, a series of analogs with a deuterated methoxy group in place of methoxy group at C-8 position was evaluated for isotope effects in preclinical assays; including microsomal stability, cytotoxicity, and sensorimotor impairment. The deuterated compounds were equally or more metabolically stable than the corresponding non-deuterated analogs and increased sensorimotor impairment was observed for some deuterated compounds. Thioesters were more cytotoxic in comparison to other carboxylic acid derivatives of this compound series. The most promising compound 16 identified from the in vitro screens also strongly inhibited smooth muscle constriction in ex vivo guinea pig tracheal rings. Smooth muscle relaxation, determined by reduction of airway hyperresponsiveness with a murine ovalbumin sensitized and challenged model, showed that 16 was efficacious at low methacholine concentrations. However, this effect was limited due to suboptimal pharmacokinetics of 16. Based on these findings, further analogs of XHE-III-74 will be investigated to improve in vivo metabolic stability while retaining the efficacy at lung tissues involved in asthma pathology.


Assuntos
Asma/tratamento farmacológico , Benzodiazepinas/farmacologia , Receptores de GABA-A/metabolismo , Animais , Benzodiazepinas/química , Benzodiazepinas/uso terapêutico , Constrição Patológica/tratamento farmacológico , Deutério/farmacologia , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Cobaias , Cloreto de Metacolina/farmacologia , Camundongos , Hipersensibilidade Respiratória/tratamento farmacológico , Relação Estrutura-Atividade , Ésteres do Ácido Sulfúrico/farmacologia , Traqueia/efeitos dos fármacos , Traqueia/patologia
12.
Mol Cancer Ther ; 15(11): 2709-2721, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27535974

RESUMO

Despite the many advances in the treatment of hematologic malignancies over the past decade, outcomes in refractory lymphomas remain poor. One potential strategy in this patient population is the specific targeting of IL2R-α (CD25), which is overexpressed on many lymphoma and leukemic cells, using antibody-drug conjugates (ADC). ADCT-301 is an ADC composed of human IgG1 HuMax-TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead with a drug-antibody ratio (DAR) of 2.3. ADCT-301 binds human CD25 with picomolar affinity. ADCT-301 has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma cell lines. Once internalized, the released warhead binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. A strong correlation between loss of viability and DNA cross-link formation is demonstrated. DNA damage persists, resulting in phosphorylation of histone H2AX, cell-cycle arrest in G2-M, and apoptosis. Bystander killing of CD25-negative cells by ADCT-301 is also observed. In vivo, a single dose of ADCT-301 results in dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models. In xenografts of Karpas 299, which expressed both CD25 and CD30, marked superiority over brentuximab vedotin (Adcetris) is observed. Dose-dependent increases in DNA cross-linking, γ-H2AX, and PBD payload staining were observed in tumors in vivo indicating a role as relevant pharmacodynamic assays. Together, these data support the clinical testing of this novel ADC in patients with CD25-expressing tumors. Mol Cancer Ther; 15(11); 2709-21. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas , Neoplasias Hematológicas/metabolismo , Imunoconjugados/farmacologia , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Pirróis , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzodiazepinas/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Histonas/metabolismo , Humanos , Imunoconjugados/química , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos , Pirróis/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Sci Rep ; 6: 25943, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-27198062

RESUMO

GABAA receptors are the main inhibitory neurotransmitter receptors in the brain and are targets for numerous clinically important drugs such as benzodiazepines, anxiolytics and anesthetics. We previously identified novel ligands of the classical benzodiazepine binding pocket in α1ß2γ2 GABAA receptors using an experiment-guided virtual screening (EGVS) method. This screen also identified novel ligands for intramembrane low affinity diazepam site(s). In the current study we have further characterized compounds 31 and 132 identified with EGVS as well as 4-O-methylhonokiol. We investigated the site of action of these compounds in α1ß2γ2 GABAA receptors expressed in Xenopus laevis oocytes using voltage-clamp electrophysiology combined with a benzodiazepine site antagonist and transmembrane domain mutations. All three compounds act mainly through the two ß+/α- subunit transmembrane interfaces of the GABAA receptors. We then used concatenated receptors to dissect the involvement of individual ß+/α- interfaces. We further demonstrated that these compounds have anesthetic activity in a small aquatic animal model, Xenopus laevis tadpoles. The newly identified compounds may serve as scaffolds for the development of novel anesthetics.


Assuntos
Anestésicos/farmacologia , Benzodiazepinas/química , Receptores de GABA-A/metabolismo , Xenopus laevis/metabolismo , Regulação Alostérica/efeitos dos fármacos , Anestésicos/química , Animais , Benzodiazepinas/farmacologia , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Flumazenil/química , Flumazenil/farmacologia , Ligantes , Estrutura Molecular , Técnicas de Patch-Clamp , Proteínas de Xenopus/metabolismo
14.
J Mol Neurosci ; 58(1): 66-73, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26572534

RESUMO

Olanzapine-induced weight gain is associated with atherosclerosis, hypertension, dyslipidemia, and diabetes. We synthesized a novel antipsychotic drug (PGW5) possessing an olanzapine moiety linked to sarcosine, a glycine transporter 1 inhibitor. In this study, we compared the metabolic effects of PGW5 and olanzapine in a female rat model of weight gain. Female rats were treated daily with oral olanzapine (4 mg/kg), PGW5 (25 mg/kg), or vehicle for 16 days. Behavioral tests were conducted on days 12-14. Biochemical analyses were performed at the end of the treatment. A significant increase in body weight was observed in the olanzapine-treated group, while the PGW5 group did not differ from the controls. The open field test showed hypo-locomotion in the olanzapine-treated animals as compared to PGW5 and control groups. A significant increase in hypothalamic protein expression of the neuropeptide Y5 receptor and a decrease in pro-opiomelanocortin messenger ribonucleic acid (mRNA) levels were detected following PGW5 treatment, but not after olanzapine administration. PGW5 appears to possess minor metabolic effects compared with the parent compound olanzapine. The differential modulation of brain peptides associated with appetite regulation is possibly involved in the attenuation of metabolic effects by PGW5.


Assuntos
Alanina/análogos & derivados , Antipsicóticos/farmacologia , Benzodiazepinas/farmacologia , Aumento de Peso/efeitos dos fármacos , Alanina/química , Alanina/farmacologia , Animais , Antipsicóticos/química , Benzodiazepinas/química , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Olanzapina , Ratos , Ratos Wistar , Receptores de Neuropeptídeo Y/genética , Receptores de Neuropeptídeo Y/metabolismo , Sarcosina/química
15.
Nat Prod Commun ; 10(9): 1549-51, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26594756

RESUMO

A new benzodiazepine alkaloid containing terminal cyano group has been isolated from a mangrove endophytic fungus, Penicillium 299#. Structure elucidation was determined by 1D and 2D NMR spectroscopy and the absolute configuration was determined by electronic circular dichroism (ECD). The new compound showed no cytotoxic activities in vitro against human cancer lines MDA-MB-435, HepG2, HCT-116, and Calu-3.


Assuntos
Acanthaceae/microbiologia , Alcaloides/química , Benzodiazepinas/química , Penicillium/química
16.
Epilepsy Behav ; 49: 347-50, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26115606

RESUMO

Benzodiazepines (BZDs), including diazepam (DZP) and midazolam (MDZ), are drugs of choice for rapid treatment of seizure emergencies. Current approved use of these drugs involves administration via either intravenous or rectal routes. The former requires trained medical personnel, while the latter is socially unacceptable for many patients and caregivers. In recent years, efforts have been made to formulate BZDs for nasal administration. Because of the low solubility of these molecules, organic vehicles have been used to solubilize the drugs in the nasal products under development. However, organic solvents are irritating, potentially resulting in injury to nasal tissue. Here we report preliminary studies supporting a strategy in which water-soluble BZD prodrugs and a suitable converting enzyme are coadministered in an aqueous vehicle. Diazepam and midazolam prodrugs were synthesized and were readily converted to their active forms by a protease from Aspergillus oryzae. Using a permeation assay based on monolayers of Madin-Darby canine kidney II-wild type cells, we found that enzymatically produced BZDs could be maintained at high degrees of supersaturation, enabling faster transport across the membrane than can be achieved using saturated solutions. This strategy not only obviates the need for organic solvents, but it also suggests more rapid absorption and earlier peak concentrations than can be otherwise achieved. This article is part of a Special Issue entitled "Status Epilepticus".


Assuntos
Anticonvulsivantes/uso terapêutico , Benzodiazepinas/uso terapêutico , Terapia Enzimática , Pró-Fármacos/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Administração Intranasal , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/química , Aspergillus oryzae/enzimologia , Benzodiazepinas/administração & dosagem , Benzodiazepinas/química , Diazepam/administração & dosagem , Diazepam/uso terapêutico , Cães , Enzimas/administração & dosagem , Células Madin Darby de Rim Canino , Midazolam/administração & dosagem , Midazolam/uso terapêutico , Peptídeo Hidrolases/uso terapêutico , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Solubilidade
17.
Artigo em Inglês | MEDLINE | ID: mdl-25922186

RESUMO

The purpose of this study was to develop a method to analyse the concentration of multiple illegal narcotics present in dietary supplements. To this end, we established and optimised a procedure using LC-MS/MS simultaneously to analyse 28 narcotic compounds in various forms of dietary supplements, including powders, tablets, liquids and capsules. In addition, candy and cookies that have also had detected cases of adulteration were also analysed. The specificity, linearity, accuracy, precision, limit of detection (LOD), limit of quantitation (LOQ), stability and recovery for these methods were validated accordingly. The LOD and LOQ of the LC-MS/MS ranged from 0.01-50.0 to 0.03-100 ng g(-1), respectively. The linearity of these results was good (r(2) > 0.99), with intra- and inter-day precision values of 0.2-5.2% and 0.2-4.8%, respectively. Further, the intra- and inter-day accuracies of this method were 97.0-103.4% and 94.6-103.1%, respectively. The stability RSD was less than 7.8%. The mean recovery for this LC-MS/MS procedure was 81.1-117.4%, with an RSD less than 9.8%. Following the validation of our method, we analysed 47 commercially available dietary supplements obtained in Korea. Whilst none of these samples had detectable amounts of the 28 specified narcotic adulterants, our novel LC-MS/MS procedure can be utilised comprehensively and continually to monitor illegal drug adulteration in various forms of dietary supplements.


Assuntos
Cromatografia Líquida/métodos , Suplementos Nutricionais/análise , Análise de Alimentos/métodos , Contaminação de Alimentos/análise , Entorpecentes/química , Espectrometria de Massas em Tandem/métodos , Benzodiazepinas/química , Estimulantes do Sistema Nervoso Central/química
18.
Bioorg Med Chem Lett ; 25(6): 1338-42, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25677667
19.
J Theor Biol ; 343: 113-9, 2014 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-24211527

RESUMO

Ribosomal phosphoprotein P1 (RPP1) is acidic phosphoprotein which in association with neutral phosphoprotein P0 and acidic phosphoprotein P2 forms ribosomal P protein complex as (P1)2-P0-(P2)2. P protein is known to be immunogenic and has important role in protein translation. 3D structure of P1 is not known. We have built an ab-initio model of RPP1 of Plasmodium falciparum using I-TASSER. Stereochemical stability of structure was checked using PROCHECK and the normality of the local environment of amino acids was checked using WHATIF. Comparison between known protein structures in PDB database and model protein was done using Dali server. Molecular dynamic simulation study and virtual screening of RPP1 was carried out. Three dimensional model structure of RPP1 was generated and model validation studies proved the model to be steriochemically significant. RPP1 structure was found to be stable at room temperature in water environment demonstrated by 30 ns molecular dynamic simulation study. Dali superimposition showed 69% superimposition to known 3D structures in PDB. Further virtual screening and docking studies promoted good interaction of ligands Ecgonine, Prazepam and Ethyl loflazepate with RPP1. The work provides insight for molecular understanding of RPP1 of P. falciparum and can be used for development of antimalarial drugs.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Simulação de Dinâmica Molecular , Fosfoproteínas/metabolismo , Plasmodium falciparum/metabolismo , Proteínas Ribossômicas/metabolismo , Interface Usuário-Computador , Sequência de Aminoácidos , Benzodiazepinas/química , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacologia , Dados de Sequência Molecular , Fosfoproteínas/química , Plasmodium falciparum/efeitos dos fármacos , Proteínas Ribossômicas/química , Subunidades Ribossômicas Maiores de Eucariotos/metabolismo , Termodinâmica
20.
Cell Physiol Biochem ; 32(1): 11-24, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23867750

RESUMO

BACKGROUND/AIMS: ATP-gated P2X4 purinergic receptors (P2X4Rs) are cation channels with important roles in diverse cell types. To date, lack of specific inhibitors has hampered investigations on P2X4Rs. Recently, the benzodiazepine derivative, 5-BDBD has been proposed to selectively inhibit P2X4Rs. However, limited evidences are currently available on its inhibitory properties. Thus, we aimed to characterize the inhibitory effects of 5-BDBD on recombinant human P2X4Rs. METHODS: We investigated ATP-induced intracellular Ca(2+) signals and whole cell ion currents in HEK 293 cells that were either transiently or stably transfected with hP2X4Rs. RESULTS: Our data show that ATP (< 1 µM) stimulates P2X4R-mediated Ca(2+) influx while endogenously expressed P2Y receptors are not activated to any significant extent. Both 5-BDBD and TNP-ATP inhibit ATP-induced Ca(2+) signals and inward ion currents in a concentration-dependent manner. Application of two different concentrations of 5-BDBD causes a rightward shift in ATP dose-response curve. Since the magnitude of maximal stimulation does not change, these data suggest that 5-BDBD may competitively inhibit the P2X4Rs. CONCLUSIONS: Our results demonstrate that application of submicromolar ATP concentrations allows reliable assessment of recombinant P2XR functions in HEK 293 cells. Furthermore, 5-BDBD and TNP-ATP have similar inhibitory potencies on the P2X4Rs although their mechanisms of actions are different.


Assuntos
Benzodiazepinas/farmacologia , Benzodiazepinonas/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X4/química , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Regulação Alostérica , Benzodiazepinas/química , Benzodiazepinonas/química , Cálcio/metabolismo , Células HEK293 , Humanos , Técnicas de Patch-Clamp , Antagonistas do Receptor Purinérgico P2X/química , Receptores Purinérgicos P2X4/genética , Receptores Purinérgicos P2X4/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Transfecção
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