Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Neurosci ; 32(25): 8532-44, 2012 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-22723693

RESUMO

M(1) muscarinic acetylcholine receptors (mAChRs) represent a viable target for treatment of multiple disorders of the central nervous system (CNS) including Alzheimer's disease and schizophrenia. The recent discovery of highly selective allosteric agonists of M(1) receptors has provided a major breakthrough in developing a viable approach for the discovery of novel therapeutic agents that target these receptors. Here we describe the characterization of two novel M(1) allosteric agonists, VU0357017 and VU0364572, that display profound differences in their efficacy in activating M(1) coupling to different signaling pathways including Ca(2+) and ß-arrestin responses. Interestingly, the ability of these agents to differentially activate coupling of M(1) to specific signaling pathways leads to selective actions on some but not all M(1)-mediated responses in brain circuits. These novel M(1) allosteric agonists induced robust electrophysiological effects in rat hippocampal slices, but showed lower efficacy in striatum and no measureable effects on M(1)-mediated responses in medial prefrontal cortical pyramidal cells in mice. Consistent with these actions, both M(1) agonists enhanced acquisition of hippocampal-dependent cognitive function but did not reverse amphetamine-induced hyperlocomotion in rats. Together, these data reveal that M(1) allosteric agonists can differentially regulate coupling of M(1) to different signaling pathways, and this can dramatically alter the actions of these compounds on specific brain circuits important for learning and memory and psychosis.


Assuntos
Comportamento Animal/efeitos dos fármacos , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Encéfalo/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Receptor Muscarínico M1/agonistas , Animais , Arrestinas/metabolismo , Células CHO , Cálcio/metabolismo , Linhagem Celular , Corpo Estriado/fisiologia , Cricetinae , Cricetulus , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Espaço Extracelular/fisiologia , Medo/psicologia , Perfilação da Expressão Gênica , Hipocampo/fisiologia , Humanos , Masculino , Aprendizagem em Labirinto , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Sprague-Dawley
2.
J Pharmacol Exp Ther ; 340(2): 404-21, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22088953

RESUMO

Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu4), including N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu4 PAMsexhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with L-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of L-DOPA, suggesting that mGlu4 PAMs may provide L-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either L-DOPA or A2A antagonists.


Assuntos
Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Ácidos Picolínicos/uso terapêutico , Receptores de Glutamato Metabotrópico/agonistas , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Antagonistas do Receptor A2 de Adenosina/sangue , Antagonistas do Receptor A2 de Adenosina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Sinalização do Cálcio/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Ácido Glutâmico/farmacologia , Células HEK293 , Haloperidol/farmacologia , Humanos , Levodopa/metabolismo , Masculino , Monoaminoxidase/metabolismo , Doença dos Neurônios Motores/induzido quimicamente , Doença dos Neurônios Motores/tratamento farmacológico , Doença dos Neurônios Motores/metabolismo , Doença dos Neurônios Motores/patologia , Doença dos Neurônios Motores/fisiopatologia , Oxidopamina/farmacologia , Ácidos Picolínicos/sangue , Ácidos Picolínicos/metabolismo , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/farmacologia , Ligação Proteica , Desempenho Psicomotor/efeitos dos fármacos , Pirimidinas/sangue , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Glutamato Metabotrópico/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...