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1.
J Med Chem ; 62(7): 3228-3250, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30893553

RESUMO

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

2.
J Am Chem Soc ; 141(2): 774-779, 2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30605319

RESUMO

A two-step degradation-reconstruction approach to the carbon-14 radiolabeling of alkyl carboxylic acids is presented. Simple activation via redox-active ester formation was followed by nickel-mediated decarboxylative carboxylation to afford a range of complex compounds with ample isotopic incorporations for drug metabolism and pharmacokinetic studies. The practicality and operational simplicity of the protocol were demonstrated by its use in an industrial carbon-14 radiolabeling setting.

3.
Protein Eng Des Sel ; 31(5): 159-171, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30247737

RESUMO

Tumor-specific delivery of cytotoxic agents remains a challenge in cancer therapy. Antibody-drug conjugates (ADC) deliver their payloads to tumor cells that overexpress specific tumor-associated antigens-but the multi-day half-life of ADC leads to high exposure even of normal, antigen-free, tissues and thus contributes to dose-limiting toxicity. Here, we present Adnectin-drug conjugates, an alternative platform for tumor-specific delivery of cytotoxic payloads. Due to their small size (10 kDa), renal filtration eliminates Adnectins from the bloodstream within minutes to hours, ensuring low exposure to normal tissues. We used an engineered cysteine to conjugate an Adnectin that binds Glypican-3, a membrane protein overexpressed in hepatocellular carcinoma, to a cytotoxic derivative of tubulysin, with the drug-to-Adnectin ratio of 1. We demonstrate specific, nanomolar binding of this Adnectin-drug conjugate to human and murine Glypican-3; its high thermostability; its localization to target-expressing tumor cells in vitro and in vivo, its fast clearance from normal tissues and its efficacy against Glypican-3-positive mouse xenograft models.


Assuntos
Glipicanas/metabolismo , Imunoconjugados/química , Neoplasias/metabolismo , Sequência de Aminoácidos , Animais , Estabilidade de Medicamentos , Feminino , Células HEK293 , Humanos , Imunoconjugados/farmacocinética , Camundongos , Distribuição Tecidual
4.
J AOAC Int ; 101(3): 891-896, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29191256

RESUMO

The U.S. Department of Agriculture, Food Safety Inspection Service regulatory method for monensin, Chemistry Laboratory Guidebook CLG-MON, is a semiquantitative bioautographic method adopted in 1991. Official Method of AnalysisSM (OMA) 2011.24, a modern quantitative and confirmatory LC-tandem MS method, uses no chlorinated solvents and has several advantages, including ease of use, ready availability of reagents and materials, shorter run-time, and higher throughput than CLG-MON. Therefore, a bridging study was conducted to support the replacement of method CLG-MON with OMA 2011.24 for regulatory use. Using fortified bovine tissue samples, CLG-MON yielded accuracies of 80-120% in 44 of the 56 samples tested (one sample had no result, six samples had accuracies of >120%, and five samples had accuracies of 40-160%), but the semiquantitative nature of CLG-MON prevented assessment of precision, whereas OMA 2011.24 had accuracies of 88-110% and RSDr of 0.00-15.6%. Incurred residue results corroborated these results, demonstrating improved accuracy (83.3-114%) and good precision (RSDr of 2.6-20.5%) for OMA 2011.24 compared with CLG-MON (accuracy generally within 80-150%, with exceptions). Furthermore, χ2 analysis revealed no statistically significant difference between the two methods. Thus, the microbiological activity of monensin correlated with the determination of monensin A in bovine tissues, and OMA 2011.24 provided improved accuracy and precision over CLG-MON.


Assuntos
Cromatografia Líquida/métodos , Contaminação de Alimentos/análise , Testes de Sensibilidade Microbiana/métodos , Monensin/análise , Espectrometria de Massas em Tandem/métodos , Animais , Bovinos , Fígado/química
5.
J AOAC Int ; 99(2): 565-70, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26961063

RESUMO

Lilly Method AM-AA-CA-R108-AB-755, which is substantially the same as U.S. Department of Agriculture, Food Safety and Inspection Service (FSIS) Chemistry Laboratory Guidebook (CLG) method R22, is the current regulatory method for determining narasin in cattle and chicken tissues and is based on bioautography, creating a zone of inhibition of bacterial growth, with the size of the zone correlating to the amount of narasin extracted from the tissue. AOAC Method 2011.24 is an LC-tandem mass spectrometry (MS/MS) method for determining narasin content from bovine, swine, or chicken tissues. It has many advantages over the regulatory method, including higher throughput, less solvent use, no use of carbon tetrachloride, a wider method range, inclusion of swine tissues, and it is less labor intensive. In this study, AOAC Method 2011.24 was compared to FSIS CLG method R22 for the determination of narasin in chicken abdominal fat. Fortified chicken-fat samples ranging from 20 to 960 ng/g and incurred chicken-fat samples ranging from 40 to 480 ng/g were assayed by both methods in triplicate. Mean accuracies for the two methods were similar, 77-110% for CLG R22 and 84-96% for AOAC Method 2011.24, and the method results showed a linear correlation. The methods differed in precision, however, with the CLG R22 method yielding 2.6-34% RSD and AOAC Method 2011.24 yielding 0.15-6.4% RSD. It is recommended that AOAC Method 2011.24-granted AOAC Official Method(SM) Final Action status-be adopted as the official U.S. regulatory method.


Assuntos
Gorduras/química , Piranos/análise , Espectrometria de Massas em Tandem , Animais , Galinhas , Cromatografia Líquida
7.
Bioorg Med Chem Lett ; 19(10): 2835-9, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19361985

RESUMO

We have developed and characterized [(35)S]4a as a potent and selective radioligand for melanin-concentrating hormone 1-receptor (MCH1R). Compound [(35)S]4a showed appreciable specific signals in brain slices prepared from wild-type mice but not from MCH1R deficient mice, confirming the specificity and utility of [(35)S]4a as a selective MCH1R radioligand for ex vivo receptor occupancy assays.


Assuntos
Benzofuranos/química , Receptores de Somatostatina/metabolismo , Compostos de Espiro/química , Sulfonamidas/química , Sequência de Aminoácidos , Animais , Benzofuranos/síntese química , Benzofuranos/farmacologia , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Cinética , Camundongos , Camundongos Knockout , Receptores de Somatostatina/antagonistas & inibidores , Receptores de Somatostatina/deficiência , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia
8.
Nucl Med Biol ; 35(3): 315-25, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18355687

RESUMO

INTRODUCTION: In an effort to develop agents to test the NMDA hypofunction hypothesis of schizophrenia, benchmark compounds from a program to discover potent, selective, competitive glycine transporter 1 (GlyT1) inhibitors were radiolabeled in order to further study the detailed pharmacology of these inhibitors and the distribution of GlyT1 in brain. We here report the in vitro characterization of [35S](S)-2-amino-4-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl)ethyl)benzamide ([35S]ACPPB), a radiotracer developed from a potent and selective non-sarcosine-derived GlyT1 inhibitor, its use in autoradiographic studies to localize (S)-2-amino-6-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl)ethyl)benzamide (ACPPB) binding sites in rat and rhesus brain and for in vivo occupancy assays of competitive GlyT1 inhibitors. METHODS: Functional potencies of unlabeled compounds were characterized by [14C]glycine uptake into JAR (human placental choriocarcinoma) cells and synaptosomes. Radioligand binding studies were performed with tissue homogenates. Autoradiographic studies were performed on tissue slices. RESULTS: ACPPB is a potent (Kd=1.9 nM), selective, GlyT1 inhibitor that, when radiolabeled with [35S], is a well-behaved radioligand with low nondisplaceable binding. Autoradiographic studies of rat and rhesus brain slices with this ligand showed that specific binding sites were plentiful and nonhomogeneously distributed, with high levels of binding in the brainstem, cerebellar white matter, thalamus, cortical white matter and spinal cord gray matter. In vivo studies demonstrate displaceable binding of [35S]ACPPB in rat brain tissues following iv administration of this radioligand. CONCLUSIONS: This is the first report of detailed anatomical localization of GlyT1 using direct radioligand binding, and the first demonstration that an in vivo occupancy assay is feasible, suggesting that it may also be feasible to develop positron emission tomography tracers for GlyT1.


Assuntos
Benzamidas/síntese química , Benzamidas/farmacocinética , Encéfalo/diagnóstico por imagem , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Animais , Autorradiografia , Benzamidas/química , Ligação Competitiva , Radioisótopos de Carbono/farmacocinética , Linhagem Celular Tumoral , Coriocarcinoma/diagnóstico por imagem , Feminino , Glicina/farmacocinética , Humanos , Macaca mulatta , Gravidez , Ensaio Radioligante , Cintilografia , Compostos Radiofarmacêuticos/química , Ratos , Ratos Sprague-Dawley , Sulfonamidas/química , Radioisótopos de Enxofre/farmacocinética , Sinaptossomos/diagnóstico por imagem , Distribuição Tecidual
9.
Drug Metab Dispos ; 34(9): 1457-61, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16772365

RESUMO

MK-0767 (KRP-297; 2-methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) is a thiazolidinedione (TZD)-containing dual agonist of the peroxisome proliferator-activated receptors alpha and gamma that has been studied as a potential treatment for patients with type 2 diabetes. The metabolism and excretion of [14C]MK-0767 were evaluated in six human volunteers after a 5-mg (200 microCi) oral dose. Excretion of 14C radioactivity was found to be nearly equal into the urine (approximately 50%) and feces (approximately 40%). Elimination of [14C]MK-0767 was primarily by metabolism, with minimal excretion of parent compound into the urine (<0.5% of dose) and feces (approximately 14% of the dose). [14C]MK-0767 was the major circulating compound-related entity (>96% of radioactivity) through 48 h postdose. It was also found that approximately 91% of the total radioactivity area under the curve was due to intact MK-0767. Several minor metabolites were detected in plasma (<1% of radioactivity, each), formed by cleavage of the TZD ring and subsequent S-methylation and oxidation. All the metabolites excreted into urine were formed by TZD cleavage, whereas the major metabolite in feces was the O-demethylated derivative of MK-0767.


Assuntos
Hipoglicemiantes/farmacologia , Tiazóis/farmacocinética , Absorção , Administração Oral , Adolescente , Adulto , Biotransformação , Radioisótopos de Carbono , Fezes/química , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/urina , Masculino , Pessoa de Meia-Idade , Tiazóis/administração & dosagem , Tiazóis/urina
10.
Chem Res Toxicol ; 18(5): 880-8, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15892582

RESUMO

Thiazolidinedione (TZD) derivatives have been reported to undergo metabolic activation of the TZD ring to produce reactive intermediates. In the case of troglitazone, it was proposed that a P450-mediated S-oxidation leads to TZD ring scission and the formation of a sulfenic acid intermediate, which may be trapped as a GSH conjugate. In the present study, we employed a model compound {denoted MRL-A, (+/-)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethoxy)phenyl]methyl]benzamide} to investigate the mechanism of TZD ring scission. When MRL-A was incubated with monkey liver microsomes (or recombinant P450 3A4 and NADPH-P450 reductase) in the presence of NADPH and oxygen, the major products of TZD ring scission were the free thiol metabolite (M2) and its dimer (M3). Furthermore, a GSH conjugate of M2 (M4) also was formed when the incubation mixture was supplemented with GSH. Experiments with isolated M2 suggested that this metabolite was unstable and underwent spontaneous autooxidation to M3. A qualitatively similar metabolite profile was observed when MRL-A was incubated with recombinant P450 3A4 and cumene hydroperoxide. Because an oxygen atom is transferred to MRL-A under these conditions, these data suggested that S-oxidation alone may result in TZD ring scission and formation of M2 via a sulfenic acid intermediate. Also, because the latter incubation mixture did not contain any reducing agents, the formation of M2 may have occurred due to disproportionation of the sulfenic acid. When NADPH was added to the incubation mixture containing P450 3A4 and cumene hydroperoxide, the formation of M3 increased, suggesting that the sulfenic acid was reduced to M2 by NADPH and subsequently underwent dimerization to yield M3 (vide supra). When NADPH was replaced by GSH, the formation of M4 increased, consistent with reduction of the sulfenic acid by GSH. In summary, these results suggest that the TZD ring in MRL-A is activated by an initial P450-mediated S-oxidation step followed by spontaneous scission of the TZD ring to a putative sulfenic acid intermediate; the latter species then undergoes reduction to the free thiol by GSH, NADPH, and/or disproportionation. Finally, the thiol may dimerize to the corresponding disulfide or, in the presence of S-adenosylmethionine, form the stable S-methyl derivative.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo , Tiazolidinedionas/metabolismo , Animais , Benzamidas/química , Benzamidas/metabolismo , Derivados de Benzeno/metabolismo , Dimerização , Dissulfetos/química , Dissulfetos/metabolismo , Glutationa/metabolismo , Haplorrinos , Microssomos Hepáticos/enzimologia , Modelos Químicos , NADP/metabolismo , Oxirredução , Oxigênio/metabolismo , S-Adenosilmetionina/química , S-Adenosilmetionina/metabolismo , Compostos de Sulfidrila/química , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia
12.
Eur J Pharmacol ; 499(1-2): 77-84, 2004 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-15363953

RESUMO

Compound A (N-[2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl]-2-[(2R)-1-(2-napthylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetamide) is a member of a new class of aryl sulfonamide dihydroquinoxalinone bradykinin B1 receptor antagonists that should be useful pharmacological tools. Here we report on some of the pharmacological properties of compound A as well as the characterization of [35S]compound A as the first nonpeptide bradykinin B1 receptor radioligand. Compound A inhibited tritiated peptide ligand binding to the cloned human, rabbit, dog, and rat bradykinin B1 receptors expressed in CHO cells with Ki values of 0.016, 0.050, 0.56, and 29 nM, respectively. It was inactive at 10 microM in binding assays with the cloned human bradykinin B2 receptor. In functional antagonist assays with the cloned bradykinin B1 receptors, compound A inhibited agonist-induced signaling with activities consistent with the competition binding results, but had no antagonist activity at the bradykinin B2 receptor. Compound A was also found to be a potent antagonist in a rabbit aorta tissue bath preparation and to effectively block des-Arg9 bradykinin depressor responses in lipopolysaccharide-treated rabbit following intravenous administration. The binding of [35S]compound A was evaluated with the cloned bradykinin B1 receptors. In assays with human, rabbit, and dog receptors, [35S]compound A labeled a single site with Kd values of 0.012, 0.064, and 0.37 nM, respectively, and with binding site densities equivalent to those obtained using the conventional tritiated peptide ligands. Binding assays with the cloned rat bradykinin B1 receptor were not successful, presumably due to the low affinity of the ligand for this species receptor. There was no specific binding of the ligand detected in CHO cells expressing the human bradykinin B2 receptor. In assays with the cloned human bradykinin B1 receptor, the pharmacologies of the binding of [35S]compound A and [3H][Leu9]des-Arg10-kallidin were the same. The high signal-to-noise ratio obtained with [35S]compound A will allow this ligand to be a very useful tool for future investigations of the bradykinin B1 receptor.


Assuntos
Antagonistas de Receptor B1 da Bradicinina , Calidina/análogos & derivados , Receptor B1 da Bradicinina/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Ligação Competitiva/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Cães , Relação Dose-Resposta a Droga , Humanos , Imidazóis/metabolismo , Imidazóis/farmacologia , Técnicas In Vitro , Calidina/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Quinoxalinas/metabolismo , Quinoxalinas/farmacologia , Coelhos , Ensaio Radioligante , Ratos , Receptor B1 da Bradicinina/genética , Transfecção , Trítio , Vasoconstrição/efeitos dos fármacos
13.
Drug Metab Dispos ; 32(11): 1254-9, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15286054

RESUMO

The technique of accelerator mass spectrometry (AMS) was validated successfully and used to study the pharmacokinetics and disposition in dogs of a preclinical drug candidate (7-deaza-2'-C-methyl-adenosine; Compound A), after oral and intravenous administration. The primary objective of this study was to examine whether Compound A displayed linear kinetics across subpharmacological (microdose) and pharmacological dose ranges in an animal model, before initiation of a human microdose study. The AMS-derived disposition properties of Compound A were comparable to data obtained via conventional techniques such as liquid chromatography-tandem mass spectrometry and liquid scintillation counting analyses. Compound A displayed multiphasic kinetics and exhibited low plasma clearance (5.8 ml/min/kg), a long terminal elimination half-life (17.5 h), and high oral bioavailability (103%). Currently, there are no published comparisons of the kinetics of a pharmaceutical compound at pharmacological versus subpharmacological doses using microdosing strategies. The present study thus provides the first description of the full pharmacokinetic profile of a drug candidate assessed under these two dosing regimens. The data demonstrated that the pharmacokinetic properties of Compound A following dosing at 0.02 mg/kg were similar to those at 1 mg/kg, indicating that in the case of Compound A, the pharmacokinetics in the dog appear to be linear across this 50-fold dose range. Moreover, the exceptional sensitivity of AMS provided a pharmacokinetic profile of Compound A, even after a microdose, which revealed aspects of the disposition of this agent that were inaccessible by conventional techniques.


Assuntos
Nucleosídeos/administração & dosagem , Nucleosídeos/farmacocinética , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Animais , Cromatografia Líquida/métodos , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Masculino , Espectrometria de Massas/métodos , Nucleosídeos/análise , Preparações Farmacêuticas/análise
14.
Drug Metab Dispos ; 32(8): 848-61, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15258111

RESUMO

Compound A (3-[2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyrindin-2-yl)propyl]-imidazolidin-1-yl]-3(S)-(6-methoxy-pyridin-3-yl)-propionic acid), a potent and selective antagonist of integrin alpha(v)beta(3) receptor, is under development for treatment of osteoporosis. This study describes metabolism and excretion of A in vivo in rats, dogs, and monkeys, and metabolism of A in vitro in primary hepatocytes from rats, dogs, monkeys, and humans. In all three animal species studied, A was primarily excreted as unchanged drug and, to a lesser degree, as phase I and phase II metabolites. Major biotransformation pathways of A included glucuronidation/glucosylation on the carboxylic group to form acyl-linked glucuronides/glucosides; and oxidation on the tetrahydronaphthyridine moiety to generate a carbinolamine and its further metabolized products. Minor pathways involved O-demethylation and hydroxylations on the alkyl chain. Only in rats, a glutathione adduct of A was also observed, and its formation is proposed to be via an iminium intermediate on the tetrahydronaphthyridine ring. Similar metabolic pathways were observed in the incubates of hepatocytes from the corresponding animals as well as from humans. CYP 3A and 2D subfamilies were capable of metabolizing A to its oxidative products. Overall, these in vitro and in vivo findings should provide useful insight on possible biotransformation pathways of A in humans.


Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/metabolismo , Animais , Cães , Feminino , Integrina alfaVbeta3/análise , Macaca mulatta , Masculino , Ratos , Ratos Sprague-Dawley
15.
Biochemistry ; 41(20): 6548-60, 2002 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-12009920

RESUMO

35S-labeled derivatives of the insecticides nodulisporic acid and ivermectin were synthesized and demonstrated to bind with high affinity to a population of receptors in Drosophila head membranes that were previously shown to be associated with a glutamate-gated chloride channel. Nodulisporic acid binding was modeled as binding to a single population of receptors. Ivermectin binding was composed of at least two kinetically distinct receptor populations, only one of which was associated with nodulisporic acid binding. The binding of these two ligands was modulated by glutamate, ivermectin, and antagonists of invertebrate gamma-aminobutyric acid (GABA)ergic receptors. Because solubilized nodulisporic acid and ivermectin receptors comigrated as 230-kDa complexes by gel filtration, antisera specific for both the Drosophila glutamate-gated chloride channel subunit GluCl alpha (DmGluCl alpha) and the GABA-gated chloride channel subunit Rdl (DmRdl) proteins were generated and used to examine the possible coassembly of these two subunits within a single receptor complex. DmGluCl alpha antibodies immunoprecipitated all of the ivermectin and nodulisporic acid receptors solubilized by detergent from Drosophila head membranes. DmRdl antibodies also immunoprecipitated all solubilized nodulisporic receptors, but only approximately 70% of the ivermectin receptors. These data suggest that both DmGluCl alpha and DmRdl are components of nodulisporic acid and ivermectin receptors, and that there also exists a distinct class of ivermectin receptors that contains the DmGluCl alpha subunit but not the DmRdl subunit. This co-association of DmGluCl alpha and DmRdl represents the first biochemical and immunological evidence of coassembly of subunits from two different subclasses of ligand-gated ion channel subunits.


Assuntos
Canais de Cloreto/metabolismo , Proteínas de Drosophila/fisiologia , Ácido Glutâmico/fisiologia , Indóis/metabolismo , Ivermectina/metabolismo , Receptores de Droga/metabolismo , Receptores de GABA-A/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Sítios de Ligação , Membrana Celular/metabolismo , Proteínas de Drosophila/química , Drosophila melanogaster , Soros Imunes/metabolismo , Ativação do Canal Iônico , Testes de Precipitina , Ensaio Radioligante , Receptores de Droga/imunologia , Solubilidade , Radioisótopos de Enxofre/metabolismo
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