Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
Biomed Pharmacother ; 153: 113359, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35785702

RESUMO

Inhibitors of dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) are effective treatments for neuropsychiatric diseases. Dasotraline [(1R,4 S)- 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-naphthalenamine, also known as SEP-225289) was evaluated for its inhibitory potency at DAT, NET and SERT using in vitro and in vivo assays. In vitro radiometric functional uptake studies showed preferential inhibition by dasotraline of hDAT (IC50 =3 nM) and hNET (IC50 =4 nM relative to hSERT(IC50 =15 nM). In mouse ex vivo occupancy studies, dasotraline demonstrated total plasma concentration-dependent occupancy at DAT, NET and SERT. Determination of the TO50 (50% transporter occupancy) were 32, 109 and 276 ng/ml, respectively. In SPECT imaging studies in baboons, dasotraline (0.2 mg/kg iv) displaced radiotracer binding to DAT by 87% but only 20% at NET and SERT. Rat microdialysis studies were performed in prefrontal cortex and striatum. Dasotraline produced sustained (>4 h) increases in dopamine and norepinephrine concentrations. Dasotraline was also more potent at increasing synaptic dopamine in the striatum, and norepinephrine in the prefrontal cortex than serotonin in these regions. In summary, dasotraline preferentially inhibits DAT and NET relative to SERT. Together, the occupancy and neurochemical profile of dasotraline provide a mechanistic basis for the treatment of diseases that have an underlying causality involving dopamine and norepinephrine dysfunction.


Assuntos
Dopamina , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , 1-Naftilamina/análogos & derivados , Animais , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Camundongos , Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ratos , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
2.
J Biomol Screen ; 20(10): 1218-31, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26296926

RESUMO

Genome-wide association studies have linked polymorphisms in the gene G72 to schizophrenia risk in several human populations. Although controversial, biochemical experiments have suggested that the mechanistic link of G72 to schizophrenia is due to the G72 protein product, pLG72, exerting a regulatory effect on human D-amino acid oxidase (hDAAO) activity. In an effort to identify hDAAO inhibitors of novel mechanism of action, we designed a pLG72-directed hDAAO activity assay suitable for high-throughput screening (HTS). During assay development, we confirmed that pLG72 was an inhibitor of hDAAO. Thus, our assay employed an IC20 pLG72 concentration that was high enough to allow dynamic pLG72-hDAAO complexes to form but with sufficient remaining hDAAO activity to measure during an HTS. After conducting an approximately 150,000-compound HTS, we further characterized a class of compound hits that were less potent hDAAO inhibitors when pLG72 was present. Focusing primarily on compound 2: [2-(2,5-dimethylphenyl)-6-fluorobenzo[d]isothiazol-3(2H)-on], we demonstrated that these compounds inhibited hDAAO via an allosteric, covalent mechanism. Although there is significant interest in the therapeutic potential of compound 2: and its analogues, their sensitivity to reducing agents and their capacity to bind cysteines covalently would need to be addressed during therapeutic drug development.


Assuntos
Proteínas de Transporte/metabolismo , D-Aminoácido Oxidase/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Esquizofrenia/tratamento farmacológico , Sítio Alostérico/efeitos dos fármacos , D-Aminoácido Oxidase/química , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neuralgia/tratamento farmacológico
3.
Biosci Rep ; 34(4)2014 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-25001371

RESUMO

The NMDAR (N-methyl-D-aspartate receptor) is a central regulator of synaptic plasticity and learning and memory. hDAAO (human D-amino acid oxidase) indirectly reduces NMDAR activity by degrading the NMDAR co-agonist D-serine. Since NMDAR hypofunction is thought to be a foundational defect in schizophrenia, hDAAO inhibitors have potential as treatments for schizophrenia and other nervous system disorders. Here, we sought to identify novel chemicals that inhibit hDAAO activity. We used computational tools to design a focused, purchasable library of compounds. After screening this library for hDAAO inhibition, we identified the structurally novel compound, 'compound 2' [3-(7-hydroxy-2-oxo-4-phenyl-2H-chromen-6-yl)propanoic acid], which displayed low nM hDAAO inhibitory potency (Ki=7 nM). Although the library was expected to enrich for compounds that were competitive for both D-serine and FAD, compound 2 actually was FAD uncompetitive, much like canonical hDAAO inhibitors such as benzoic acid. Compound 2 and an analog were independently co-crystalized with hDAAO. These compounds stabilized a novel conformation of hDAAO in which the active-site lid was in an open position. These results confirm previous hypotheses regarding active-site lid flexibility of mammalian D-amino acid oxidases and could assist in the design of the next generation of hDAAO inhibitors.


Assuntos
Domínio Catalítico/efeitos dos fármacos , D-Aminoácido Oxidase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Proteínas de Transporte/metabolismo , Humanos , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo , Serina/metabolismo
4.
J Med Chem ; 56(9): 3710-24, 2013 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-23631755

RESUMO

We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (Kd ≈ 2-4 µM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (Kd ≈ 100-200 nM) and slow release kinetics (k < 0.01 s(-1)) in the presence of substrate, while inhibitors with pendent aromatic groups altered conformations of the active site lid, as evidenced by X-ray crystallography, and showed slower kinetics of association. Rigid bioisosteres of benzoic acid induced a closed-lid conformation, had slower release in the presence of substrate, and were more potent than benzoate. Steady-state d-serine concentrations were described in a PK/PD model, and competition for d-serine sites on NMDA receptors was demonstrated in vivo. DAAO inhibition increased the spatiotemporal influence of glial-derived d-serine, suggesting localized effects on neuronal circuits where DAAO can exert a neuromodulatory role.


Assuntos
D-Aminoácido Oxidase/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Ligação Competitiva , Domínio Catalítico , D-Aminoácido Oxidase/química , D-Aminoácido Oxidase/metabolismo , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Glicina/metabolismo , Humanos , Cinética , Masculino , Simulação de Acoplamento Molecular , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Ratos , Ratos Sprague-Dawley , Serina/biossíntese , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacocinética
6.
J Am Chem Soc ; 124(27): 7880-1, 2002 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-12095314

RESUMO

Simple and practical asymmetric synthesis of functionally differentiated aminoindanol based endo-N-sulfonyl 1,2,3-oxathiazolidine-2-oxide as sulfinyl transfer agents are developed. The importance of these new and unique sulfinyl transfer reagents are exemplified by the expedient production of several sulfinamide ligands, including either enantiomer of (R)-tert-butanesulfinamide in excellent yields and enantiopurities.


Assuntos
Amidas/síntese química , Ácidos Sulfínicos/síntese química , Óxidos de Enxofre/química , Tiazóis/química , Estereoisomerismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA