RESUMO
Wide application of gonadotropin-releasing hormone (GnRH) agonists and antagonists for clinical purposes determines their effects on ovarian signaling pathways. Our study aimed to determine the localization, expression levels of Wnt signaling members in the pubertal and adult mouse ovary and the impact of GnRH antagonist cetrorelix on these signaling members. 0.5 mg/kg of cetrorelix was injected to 3-and 6-week-old mice for 2 weeks. At the end of injection, ovaries from 5 (5Ce)- to 8-week (8Ce)-old mice were embedded in paraffin for immunohistochemistry and homogenized for western blot to compare with control (5C-8C) and sham groups (5S-8S). WNT2 and WNT4 showed higher expression in thecal and stromal cells in adult mouse ovaries and only WNT4 expression was affected by cetrorelix. FZD1 was localized mainly in oocytes of pubertal ovaries and granulosa cells and oocytes of adult ovaries. FZD1 was reduced by cetrorelix in pubertal ovaries. FZD4 was abundantly localized in thecal and stromal cells of all groups and protein level was not affected by cetrorelix. LRP-6 was expressed mainly in oocytes and stromal cells of pubertal, oocytes of adult ovaries and its expression was reduced by cetrorelix in adult ovaries. CTNNB1 intensity in granulosa cells was the lowest in pubertal and the highest in adult ovaries and its expression was decreased by cetrorelix in adult ovaries. Cetrorelix affected the expression of specific members of the Wnt signaling depending on the developmental stage of mice, pointing out its possible interaction with gonadotropins during pubertal and adult stages.
Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Antagonistas de Hormônios/farmacologia , Oócitos/efeitos dos fármacos , Puberdade/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Feminino , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/química , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/farmacologia , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/química , Camundongos , Camundongos Endogâmicos BALB C , Oócitos/metabolismo , Puberdade/metabolismoRESUMO
Studies of stress effects on the brain have traditionally focused on neurons, without considering the cerebral microcirculation. Here we report that stress impairs neurovascular coupling (NVC), the process that matches neuronal activity with increased local blood flow. A stressed phenotype was induced in male rats by administering a 7-d heterotypical stress paradigm. NVC was modeled by measuring parenchymal arteriole (PA) vasodilation in response to neuronal stimulation in amygdala brain slices. After stress, vasodilation of PAs to neuronal stimulation was greatly reduced, and dilation of isolated PAs to external K(+) was diminished, suggesting a defect in smooth muscle inwardly rectifying K(+) (KIR) channel function. Consistent with these observations, stress caused a reduction in PA KIR2.1 mRNA and smooth muscle KIR current density, and blocking KIR channels significantly inhibited NVC in control, but not in stressed, slices. Delivery of corticosterone for 7 d (without stressors) or RU486 (before stressors) mimicked and abrogated NVC impairment by stress, respectively. We conclude that stress causes a glucocorticoid-mediated decrease in functional KIR channels in amygdala PA myocytes. This renders arterioles less responsive to K(+) released from astrocytic endfeet during NVC, leading to impairment of this process. Because the fidelity of NVC is essential for neuronal health, the impairment characterized here may contribute to the pathophysiology of brain disorders with a stress component.
Assuntos
Glucocorticoides/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Transdução de Sinais , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Arteríolas/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Corticosterona/química , Glucose/metabolismo , Antagonistas de Hormônios/química , Sistema Límbico/efeitos dos fármacos , Masculino , Mifepristona/química , Neurônios/fisiologia , Oxigênio/metabolismo , Fenótipo , Ratos , Ratos Sprague-Dawley , Estresse Psicológico , Fatores de Tempo , Vasodilatação/efeitos dos fármacosRESUMO
Amyloid formation of the 37-residue amylin is involved in the pathogenesis of type 2 diabetes and, potentially, diabetes-induced neurological deficits. Numerous flavonoids exhibit inhibitory effects against amylin amyloidosis, but the mechanisms of inhibition remain unclear. Screening a library of natural compounds uncovered a potent lead compound, the flavone baicalein. Baicalein inhibits amylin amyloid formation and reduces amylin-induced cytotoxicity. Analogue analyses demonstrated, for the first time, key roles of the vicinal hydroxyl groups on the A-ring. We provided mass spectrometric evidence that incubating baicalein and amylin leads to their conjugation, consistent with a Schiff base mechanism.
Assuntos
Flavanonas/farmacologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/antagonistas & inibidores , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Diabetes Mellitus Tipo 2/etiologia , Avaliação Pré-Clínica de Medicamentos , Flavanonas/química , Antagonistas de Hormônios/química , Antagonistas de Hormônios/farmacologia , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/ultraestrutura , Espectrometria de Massas , Microscopia Eletrônica de Transmissão , Relação Estrutura-AtividadeRESUMO
To increase the selectivity of chemotherapeutic agents, receptor-mediated tumor-targeting approaches have been developed. Here, degarelix [Ac-D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2], a gonadotropin-releasing hormone antagonist, was employed as a targeting moiety for paclitaxel (PTX). Five PTX-degarelix conjugates were synthesized, in which PTX was attached via disulfide bond to the different position in the degarelix sequence. All of the PTX-degarelix conjugates exhibited a half-life greater than 10 h determined in human serum. A fluorometric imaging plate reader assay showed that the conjugates LK-MY-9 and LK-MY-10 had an antagonism efficacy similar to that of degarelix. The in vitro cytostatic effects of the conjugates were determined by a (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay, and the 50% inhibitory concentration value of the conjugates on 3T3 mouse embryonic fibroblast cells were one order of magnitude higher than the 50% inhibitory concentration values of the conjugates on MCF-7 human breast cancer cells and HT-29 human colon cancer cells. Receptor saturation tests further demonstrated that pre-incubation of the cells with degarelix reduced the efficacy of LK-MY-10 in a concentration-dependent manner. In conclusion, degarelix is a valid and stable moiety that has great potential for targeting chemotherapy drugs.
Assuntos
Antineoplásicos Fitogênicos/química , Glicoconjugados/síntese química , Antagonistas de Hormônios/química , Oligopeptídeos/química , Paclitaxel/química , Receptores LHRH/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos/química , Glicoconjugados/farmacologia , Células HT29 , Antagonistas de Hormônios/metabolismo , Antagonistas de Hormônios/farmacologia , Humanos , Concentração Inibidora 50 , Células MCF-7 , Camundongos , Terapia de Alvo Molecular , Células NIH 3T3 , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacologia , Paclitaxel/farmacologia , Ligação Proteica , Receptores LHRH/química , Receptores LHRH/metabolismoRESUMO
It is well known that GnRH analogs can self-assemble into amyloid fibrils and that the duration of action of GnRH analogs depends on the ability of the amyloid to slowly release active peptides. The aim of this study was to investigate the influence of the amino acid residues at position 7 of GnRH analogues on peptide self-assembly. It was found that the dominant shape of the nanostructure can be changed when the structures of the residues at position 7 differ significantly from that of leucine in Degarelix. When the backbone length was extended (peptide 9), or the side chain of the residue at position 7 was replaced by an aromatic ring (peptide 6), or the rotation of the amide bond was restricted (peptide 8), the nanostructure changed from fibrils to vesicles. The results also indicate that the increasing hydrophilicity had little influence on the nanostructure morphology. In addition, a suitable release rate was found to play a more important role for the duration of the peptide action by maintaining the equilibrium between the drug concentration and the persistent release time, while the nanostructure shape was found to exert little influence on the duration of the peptide action.
Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Sequência de Aminoácidos , Animais , Hormônio Liberador de Gonadotropina/química , Hormônio Liberador de Gonadotropina/farmacocinética , Antagonistas de Hormônios/química , Antagonistas de Hormônios/farmacocinética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Microscopia Eletrônica de Transmissão , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Oligopeptídeos/síntese química , Oligopeptídeos/química , Oligopeptídeos/farmacocinética , Neoplasias da Próstata/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The pleiotropic cytokine hormone leptin, by activating its receptor OB-R, plays a major role in many biological processes, including energy homeostasis, immune function, and cell survival and proliferation. Abnormal leptin action is associated with obesity, autoimmune diseases, and cancer. The pharmacological characterization of OB-R and the development of synthetic OB-R ligands are still in their infancy because currently available binding assays are not compatible with ligand saturation binding experiments and high-throughput screening (HTS) approaches. We have developed here a novel homogeneous time-resolved fluorescence-based binding assay that overcomes these limitations. In this assay, fluorescently labeled leptin or leptin antagonist binds to the SNAP-tagged OB-R covalently labeled with terbium cryptate (Tb). Successful binding is monitored by measuring the energy transfer between the Tb energy donor and the fluorescently labeled leptin energy acceptor. Ligand binding saturation experiments revealed high-affinity dissociation constants in the subnanomolar range with an excellent signal-to-noise ratio. The assay performed in a 384-well format shows high specificity and reproducibility, making it perfectly compatible with HTS applications to identify new OB-R agonists or antagonists. In addition, fluorescently labeled leptin and SNAP-tagged OB-R will be valuable tools for monitoring leptin and OB-R trafficking in cells and tissues.
Assuntos
Fluorescência , Receptores para Leptina/metabolismo , Fosfatase Alcalina/química , Fosfatase Alcalina/metabolismo , Sítios de Ligação/efeitos dos fármacos , Células Cultivadas , Células HEK293 , Ensaios de Triagem em Larga Escala , Antagonistas de Hormônios/química , Antagonistas de Hormônios/metabolismo , Antagonistas de Hormônios/farmacologia , Humanos , Leptina/antagonistas & inibidores , Leptina/química , Leptina/metabolismo , Ligantes , Ligação Proteica , Receptores para Leptina/análise , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
Early studies led to the identification of 11ß-aryl-4',5'-dihydrospiro[estra-4,9-diene-17ß,4'-oxazole] analogs with potent and more selective antiprogestational activity compared to antiglucocorticoid activity than mifepristone. In the present study, we replaced the 4'-dimethylaminophenyl group of mifepristone with the benzoxazol group to give 5a-d. We also prepared the 17ß-formamido analogs 6a,b using a new synthetic strategy via the intermediate epoxide 21. These compounds were evaluated for their antagonist hormonal properties using the T47D cell-based alkaline phosphatase assay and the A549 cell-based functional assay. Compound 5c showed potent antagonist activity at GR with better selectivity for GR versus PR than mifepristone and is a promising lead for further development.
Assuntos
Antagonistas de Hormônios/síntese química , Antagonistas de Hormônios/farmacologia , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Progesterona/antagonistas & inibidores , Esteroides/síntese química , Esteroides/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/química , Benzoxazóis/farmacologia , Linhagem Celular Tumoral , Antagonistas de Hormônios/química , Humanos , Concentração Inibidora 50 , Mifepristona/química , Estrutura Molecular , Esteroides/química , Especificidade por Substrato/efeitos dos fármacosRESUMO
The V1a receptor has emerged as an attractive target for a range of indications including Raynaud's disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective and metabolically stable V1a antagonists. In this communication, we demonstrate the series-dependent effect of limiting the number of rotatable bonds in order to decrease Cytochrome P450-mediated metabolism. This effort culminated in the discovery of PF-184563, a novel, selective V1a antagonist with excellent in vitro and in vivo properties.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Fármacos , Descoberta de Drogas , Dismenorreia/tratamento farmacológico , Antagonistas de Hormônios/síntese química , Antagonistas de Hormônios/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Benzodiazepinas/química , Benzodiazepinas/metabolismo , Estabilidade de Medicamentos , Feminino , Antagonistas de Hormônios/química , Antagonistas de Hormônios/metabolismo , Humanos , Microssomos/fisiologia , Estrutura Molecular , Triazóis/química , Triazóis/metabolismoRESUMO
A comprehensive method was developed for the simultaneous trace analysis of ten hormone antagonist pharmaceuticals (raloxifene, exemestane, letrozole, anastrozole, mifepristone, finastride, tamoxifen, N-desmethyltamoxifen, clomiphene, and toremifene) in municipal sewage and hospital wastewater samples. The target compounds were firstly extracted using an Oasis HLB cartridge, followed by purification by an aminopropyl cartridge, and were then analyzed by liquid chromatography electrospray ionization tandem mass spectrometry in positive ion mode. The recoveries for the analytes based on internal standard calibration in different test matrices ranged from 67.6 to 118.6% (with the exception of mifepristone in clinical wastewater samples), with relative standard deviations less than 20%. The method quantification limits of the ten pharmaceuticals were in the range 0.10-2.0 ng/L. Excluding exemestane and N-desmethyltamoxifen, eight drugs were detected at 0.20-195.0 ng/L in hospital wastewater and municipal wastewater samples from Beijing.
Assuntos
Cromatografia Líquida/métodos , Antagonistas de Hormônios/análise , Resíduos de Serviços de Saúde/análise , Esgotos/química , Espectrometria de Massas em Tandem/métodos , Poluentes Químicos da Água/análise , Antagonistas de Hormônios/química , Técnicas de Diluição do Indicador , Estrutura Molecular , PrótonsRESUMO
Mifepristone is one of potent anti-progesterone agents, which binds to progesterone receptors and glucocorticoid receptors. Until now, there are a lot of research focusing on enhancing the solubility and oral bioavailability of Mifepristone. However, poor solubility and oral bioavailability has some undesirable consequences. In this work, Mifepristone in form D was discovered for the first time and characterized by PXRD, TGA, DSC, FT-IR, SEM and SS NMR. Form D was a metastable crystal type which manifested favorable stability under ambient conditions. Form D had better dissolution characteristic compared with commercial Mifepristone in 0.5% SDS solution. In addition, Mifepristone in form D exhibited a 1.43-fold higher peak plasma concentration (Cmax) and 1.46-fold higher area under the curve (AUC) in rats. The work in this paper is a complement to the present understanding of drug polymorphism on the in vitro and in vivo behavior, and establishes the ground work for future development of Mifepristone in form D as a promising drug for the market.
Assuntos
Antagonistas de Hormônios/química , Antagonistas de Hormônios/farmacocinética , Mifepristona/química , Mifepristona/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Feminino , Antagonistas de Hormônios/administração & dosagem , Mifepristona/administração & dosagem , Conformação Molecular , Ratos , Ratos Sprague-Dawley , SolubilidadeRESUMO
A sensitive liquid chromatography-mass spectrometric method was validated for the quantification of RU38486 (mifepristone) in human and murine plasma. The analyte and internal standard (alfaxolone) were extracted by liquid-liquid extraction with diethyl ether, resolved on a C18 column using gradient elution with methanol and ammonium acetate and detected after positive electrospray ionization (m/z 430-->372; m/z 333-->297, respectively). Quantification was linear over the range 0.5-500ng (r(2)>0.997), precise and accurate (intra-assay RSD< or =7.2%, RME< or =8.2%; inter-assay RSD< or =15.7% RME< or =10.2%). The limit of quantification (LOQ) was 50pg injected on column, permitting reproducible analysis of RU38486 in small volumes of plasma.
Assuntos
Espectrometria de Massas/métodos , Mifepristona/sangue , Adulto , Animais , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Antagonistas de Hormônios/sangue , Antagonistas de Hormônios/química , Humanos , Masculino , Camundongos , Mifepristona/química , Peso Molecular , Solventes , TemperaturaRESUMO
The hypothalamic-pituitary-gonadal (HPG) axis, important in reproduction and sex hormone-dependent diseases, is regulated by a number of G protein-coupled receptors. The recently "deorphanized" GPR54 receptor activated by the peptide metastin is thought to be the key regulator of the axis, mainly by releasing gonadotropin-releasing hormone (GnRH) from the hypothalamus. The latter decapeptide, through the activation of the GnRH receptor in the anterior pituitary, causes the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which subsequently activate their respective receptors on the gonadotrope cells. In this review we will discuss the small molecule agonists and antagonists that are currently being developed to intervene with the action of these four receptors. For GnRH receptors, 14 different chemical classes of non-peptidic antagonists have been reported, while for the LH receptor three classes of agonists have been described. Both agonists and antagonists have been introduced for the FSH receptor. Recently, the first non-peptidic agonist for GPR54 was reported.
Assuntos
Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Oligopeptídeos/química , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores da Gonadotropina/agonistas , Receptores da Gonadotropina/antagonistas & inibidores , Animais , Hormônio Foliculoestimulante/antagonistas & inibidores , Hormônio Foliculoestimulante/metabolismo , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hormônio Liberador de Gonadotropina/metabolismo , Antagonistas de Hormônios/química , Antagonistas de Hormônios/metabolismo , Antagonistas de Hormônios/farmacologia , Humanos , Ligantes , Hormônio Luteinizante/antagonistas & inibidores , Hormônio Luteinizante/metabolismo , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacologia , Receptores do FSH/agonistas , Receptores do FSH/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores do LH/agonistas , Receptores LHRH/antagonistas & inibidoresRESUMO
Progesterone antagonists belong to the family of selective progesterone receptor modulators. SPRMs already have several applications in women's health. Their main value lies in their effect on endometrium. For example, they can be used to reduce tumor volume and uterine bleeding before uterine myoma surgery. They are also being evaluated for the treatment of endometriosis, and for estrogen-free contraception.
Assuntos
Antagonistas de Hormônios/uso terapêutico , Receptores de Progesterona/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Endometriose/tratamento farmacológico , Feminino , Antagonistas de Hormônios/química , Humanos , Leiomioma/tratamento farmacológico , Estrutura Molecular , Neoplasias Uterinas/tratamento farmacológicoRESUMO
The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR+ OVCAR5 ovarian cancer xenograft model. Clinical evaluation of safety and therapeutic potential of 28 is underway.
Assuntos
Descoberta de Drogas , Antagonistas de Hormônios/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Feminino , Antagonistas de Hormônios/química , Antagonistas de Hormônios/farmacocinética , Humanos , Camundongos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ratos , Suínos , Porco Miniatura , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Alcohol dependence is characterized by excessive alcohol consumption, loss of control over intake, and the presence of a withdrawal syndrome, which includes both motivational and physical symptoms. Similar to human alcoholics, ethanol-dependent animals display enhanced anxiety-like behaviors and enhanced ethanol self-administration during withdrawal, effects hypothesized to result from a dysregulation of corticotropin-releasing factor (CRF) stress systems. Here, we used an animal model of ethanol dependence to test the effects of CRF(1) receptor antagonists on excessive ethanol self-administration in dependent rats. METHODS: Wistar rats, trained to orally self-administer ethanol, were exposed intermittently to ethanol vapors to induce ethanol dependence. Nondependent animals were exposed to control air. Following a 2-hour period of withdrawal, dependent and nondependent animals were systemically administered antalarmin, MJL-1-109-2, or R121919 (CRF(1) antagonists) and ethanol self-administration was measured. RESULTS: The nonpeptide, small molecule CRF(1) antagonists selectively reduced excessive self-administration of ethanol in dependent animals during acute withdrawal. The antagonists had no effect on ethanol self-administration in nondependent rats. CONCLUSIONS: These data demonstrate that CRF(1) receptors play an important role in mediating excessive ethanol self-administration in dependent rats, with no effect in nondependent rats. CRF(1) antagonists may be exciting new pharmacotherapeutic targets for the treatment of alcoholism in humans.
Assuntos
Alcoolismo/tratamento farmacológico , Alcoolismo/psicologia , Depressores do Sistema Nervoso Central/administração & dosagem , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Etanol/administração & dosagem , Antagonistas de Hormônios/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Antagonistas de Hormônios/química , Masculino , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Ratos , Ratos Wistar , Autoadministração/métodos , Triazinas/uso terapêuticoRESUMO
Corcept Therapeutics Inc is developing mifepristone (as C-1073, Corlux), an orally available progesterone and glucocorticoid antagonist originally launched as an abortifacient by Aventis Pharma AG, for the potential treatment of the psychotic features of psychotic major depression (PMD) and for Alzheimer's disease (AD). In August 2004, a pivotal phase III trial was initiated in the US for psychotic features of PMD, a second trial began in October 2004 and these were followed by a European phase III trial in May 2005. However, in August 2006, September 2006 and March 2007, respectively, these phase III trials failed to meet their endpoints. A further phase III trial was to commence later in 2007. By August 2006, Corcept expected to file an NDA for PMD in 2007. In addition, in March 2005 a phase II study of mifepristone as a cognitive enhancer in AD was underway, and in May 2006 a proof-of-concept study in alleviating the weight gain associated with olanzapine had begun.
Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Glucocorticoides/antagonistas & inibidores , Mifepristona/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Animais , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Transtorno Depressivo Maior/complicações , Antagonistas de Hormônios/química , Antagonistas de Hormônios/farmacologia , Antagonistas de Hormônios/uso terapêutico , Humanos , Mifepristona/química , Mifepristona/farmacologia , Estrutura Molecular , Transtornos Psicóticos/complicaçõesRESUMO
Many drugs bind to and activate human pregnane X receptor (hPXR) to upregulate drug-metabolizing enzymes, resulting in decreased drug efficacy and increased resistance. This suggests that hPXR antagonists have therapeutic value. Here we report that SPA70 is a potent and selective hPXR antagonist. SPA70 inhibits hPXR in human hepatocytes and humanized mouse models and enhances the chemosensitivity of cancer cells, consistent with the role of hPXR in drug resistance. Unexpectedly, SJB7, a close analog of SPA70, is an hPXR agonist. X-ray crystallography reveals that SJB7 resides in the ligand-binding domain (LBD) of hPXR, interacting with the AF-2 helix to stabilize the LBD for coactivator binding. Differential hydrogen/deuterium exchange analysis demonstrates that SPA70 and SJB7 interact with the hPXR LBD. Docking studies suggest that the lack of the para-methoxy group in SPA70 compromises its interaction with the AF-2, thus explaining its antagonism. SPA70 is an hPXR antagonist and promising therapeutic tool.The xenobiotic-activated human pregnane X receptor (hPXR) regulates drug metabolism. Here the authors develop hPXR modulators, which are of potential therapeutic interest and functionally and structurally characterize the antagonist SPA70 and the structurally related agonist SJB7.
Assuntos
Antagonistas de Hormônios/farmacologia , Receptores de Esteroides/antagonistas & inibidores , Animais , Linhagem Celular , Resistência a Medicamentos , Células HEK293 , Antagonistas de Hormônios/química , Humanos , Camundongos Transgênicos , Modelos Moleculares , Receptor de Pregnano X , Receptores de Esteroides/químicaRESUMO
A broad range of pesticides have been reported to interfere with the normal function of the thyroid endocrine system. However, the precise mechanism(s) of action has not yet been thoroughly elucidated. In this study, 21 pesticides were assessed for their binding interactions and the potential to disrupt thyroid homeostasis. In the GH3 luciferase reporter gene assays, 5 of the pesticides tested had agonistic effects in the order of procymidone > imidacloprid > mancozeb > fluroxypyr > atrazine. 11 pesticides inhibited luciferase activity of T3 to varying degrees, demonstrating their antagonistic activity. And there are 4 pesticides showed mixed effects when treated with different concentrations. Surface plasmon resonance (SPR) biosensor technique was used to directly measure the binding interactions of these pesticides to the human thyroid hormone receptor (hTR). 13 pesticides were observed to bind directly with TR, with a KD ranging from 4.80E-08 M to 9.44E-07 M. The association and disassociation of the hTR/pesticide complex revealed 2 distinctive binding modes between the agonists and antagonists. At the same time, a different binding mode was displayed by the pesticides showed mix agonist and antagonist activity. In addition, the molecular docking simulation analyses indicated that the interaction energy calculated by CDOCKER for the agonists and antagonists correlated well with the KD values measured by the surface plasmon resonance assay. These results help to explain the differences of the TR activities of these tested pesticides.
Assuntos
Disruptores Endócrinos/toxicidade , Fungicidas Industriais/toxicidade , Herbicidas/toxicidade , Antagonistas de Hormônios/toxicidade , Inseticidas/toxicidade , Neoplasias Hipofisárias/metabolismo , Receptores alfa dos Hormônios Tireóideos/efeitos dos fármacos , Receptores beta dos Hormônios Tireóideos/efeitos dos fármacos , Animais , Sítios de Ligação , Técnicas Biossensoriais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Disruptores Endócrinos/química , Disruptores Endócrinos/metabolismo , Fungicidas Industriais/química , Fungicidas Industriais/metabolismo , Herbicidas/química , Herbicidas/metabolismo , Antagonistas de Hormônios/química , Antagonistas de Hormônios/metabolismo , Humanos , Inseticidas/química , Inseticidas/metabolismo , Cinética , Ligantes , Luciferases de Vaga-Lume/biossíntese , Luciferases de Vaga-Lume/genética , Simulação de Acoplamento Molecular , Neoplasias Hipofisárias/genética , Ligação Proteica , Conformação Proteica , Ratos , Medição de Risco , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Receptores alfa dos Hormônios Tireóideos/química , Receptores alfa dos Hormônios Tireóideos/genética , Receptores alfa dos Hormônios Tireóideos/metabolismo , Receptores beta dos Hormônios Tireóideos/química , Receptores beta dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/metabolismo , TransfecçãoRESUMO
Since the discovery of the progesterone receptor antagonist mifepristone, numerous additional compounds, which display a spectrum of biological actions ranging from full antagonist to those with mixed agonist/antagonist activity, have been synthesized. The latter are referred to as selective progesterone receptor modulators. Long-term administration of these agents is associated with an antiproliferative action on the endometrium as well as amenorrhea and often inhibition of ovulation. Thus far, the majority of clinical data have been obtained with mifepristone but studies are currently underway with other compounds. These compounds have application in the treatment of uterine myoma, endometriosis, dysfunctional uterine bleeding, as potential contraceptives and in steroid responsive tumors.
Assuntos
Antagonistas de Hormônios/farmacologia , Receptores de Progesterona/antagonistas & inibidores , Animais , Antagonistas de Hormônios/química , Humanos , Mifepristona/farmacologia , Receptores de Progesterona/químicaRESUMO
A novel series of steroidal compounds were designed and synthesized with various phosphorus-containing groups on the 17beta-side chain as progesterone receptor antagonists. The structure-activity relationships of these compounds are discussed. Selected compounds were tested in an rat progesterone-sensitive assay. Some of these compounds are more potent than mifepristone, with a better selectivity profile in differentiating progesterone receptor from glucocorticoid receptor.