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1.
Sci Signal ; 15(760): eabm3720, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36378750

RESUMO

Many dementias are propagated through the spread of "prion-like" misfolded proteins. This includes prion diseases themselves (such as Creutzfeldt-Jakob disease) and Alzheimer's disease (AD), for which no treatments are available to slow or stop progression. The M1 acetylcholine muscarinic receptor (M1 receptor) is abundant in the brain, and its activity promotes cognitive function in preclinical models and in patients with AD. Here, we investigated whether activation of the M1 receptor might slow the progression of neurodegeneration associated with prion-like misfolded protein in a mouse model of prion disease. Proteomic and transcriptomic analysis of the hippocampus revealed that this model had a molecular profile that was similar to that of human neurodegenerative diseases, including AD. Chronic enhancement of the activity of the M1 receptor with the positive allosteric modulator (PAM) VU0486846 reduced the abundance of prion-induced molecular markers of neuroinflammation and mitochondrial dysregulation in the hippocampus and normalized the abundance of those associated with neurotransmission, including synaptic and postsynaptic signaling components. PAM treatment of prion-infected mice prolonged survival and maintained cognitive function. Thus, allosteric activation of M1 receptors may reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Doenças Priônicas , Príons , Humanos , Animais , Camundongos , Príons/genética , Doenças Neurodegenerativas/genética , Patologia Molecular , Proteômica , Doenças Priônicas/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Receptor Muscarínico M1/genética , Receptor Muscarínico M1/metabolismo
2.
Bioorg Med Chem Lett ; 21(11): 3243-7, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21546249

RESUMO

We report the synthesis of four series of 3,5-disubstituted-phenyl ligands targeting the metabotropic glutamate receptor subtype 5: (2-methylthiazol-4-yl)ethynyl (1a-j,), (6-methylpyridin-2-yl)ethynyl (2a-j), (5-methylpyridin-2-yl)ethynyl (3a-j,), and (pyridin-2-yl)ethynyl (4a-j,). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro assay. All compounds were found to be full antagonists and exhibited low nanomolar to subnanomolar activity.


Assuntos
Acetileno/análogos & derivados , Piridinas/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tiazóis/química , Acetileno/química , Acetileno/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Células Cultivadas , Ligantes , Camundongos , Estrutura Molecular , Piridinas/farmacologia , Ratos , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-Atividade , Tiazóis/farmacologia
3.
Curr Drug Targets CNS Neurol Disord ; 1(3): 239-50, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12769617

RESUMO

The basal ganglia are implicated in a number of disorders including neurodegenerative motor diseases such as Huntington's and Parkinson's disease, as well as psychiatric disorders such as schizophrenia and obsessive compulsive disorder. In recent years, a great deal of effort has been focused on determining the basal ganglia circuitry that underlies normal behavior, as well as many of these syndromes. This has led to a detailed understanding of both the normal and pathophysiological flow of information through the basal ganglia, and has provided the opportunity to begin developing novel pharmacological methods of intervention by targeting neuromodulatory receptors with in the basal ganglia circuit. One group of receptors that holds much promise for several basal ganglia disorders is the metabotropic glutamate receptors. Data from behavioral, neurochemical, neuroanatomical and electrophysiological studies has begun to reveal the functional roles that the metabotropic glutamate receptors play in modulating the basal ganglia circuit, and suggests that compounds selectively targeting these receptors may provide novel therapies for a variety of disorders including Parkinson's disease, addiction, and epilepsy.


Assuntos
Gânglios da Base/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Gânglios da Base/efeitos dos fármacos , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/metabolismo
4.
PLoS One ; 3(5): e2155, 2008 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-18478073

RESUMO

Hippocampal synaptic plasticity and learning are strongly regulated by metabotropic glutamate receptors (mGluRs) and particularly by mGluR5. Here, we investigated the mechanisms underlying mGluR5-modulation of these phenomena. Prolonged pharmacological blockade of mGluR5 with MPEP produced a profound impairment of spatial memory. Effects were associated with 1) a reduction of mGluR1a-expression in the dentate gyrus; 2) impaired dentate gyrus LTP; 3) enhanced CA1-LTP and 4) suppressed theta (5-10 Hz) and gamma (30-100 Hz) oscillations in the dentate gyrus. Allosteric potentiation of mGluR1 after mGluR5 blockade significantly ameliorated dentate gyrus LTP, as well as suppression of gamma oscillatory activity. CA3-lesioning prevented MPEP effects on CA1-LTP, suggesting that plasticity levels in CA1 are driven by mGluR5-dependent synaptic and network activity in the dentate gyrus. These data support the hypothesis that prolonged mGluR5-inactivation causes altered hippocampal LTP levels and network activity, which is mediated in part by impaired mGluR1-expression in the dentate gyrus. The consequence is impairment of long-term learning.


Assuntos
Aprendizagem , Potenciação de Longa Duração , Receptores de Glutamato Metabotrópico/fisiologia , Regulação Alostérica , Animais , Giro Denteado/efeitos dos fármacos , Giro Denteado/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Memória , Piridinas/farmacologia , Ratos , Ratos Wistar , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/antagonistas & inibidores
5.
Anal Biochem ; 321(1): 31-7, 2003 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-12963052

RESUMO

Human placental choriocarcinoma (JAR) cells endogenously expressing glycine transporter type 1a (GlyT1a) have been cultured in 96-well scintillating microplates to develop a homogenous screening assay for the detection of GlyT1 antagonists. In these microplates uptake of [14C]glycine was time dependent and saturable with a Michaelis-Menten constant (Km) of 27+/-3 microM. The GlyT1 transport inhibitors sarcosine, ALX-5407, and Org-24598 were tested and shown to block [14C]glycine uptake with expected IC50 values of 37.5+/-4.6 microM, 2.8+/-0.6 nM, and 6.9+/-0.9 nM, respectively. The [14C]glycine uptake process was sensitive to membrane Na+ gradient as blockade of membrane Na+/K+-ATPase by ouabain or Na+ exchanger by benzamil-disrupted glycine accumulation in JAR cells. Glycine influx was not affected by concentration of dimethyl sulfoxide up to 2%. The versatility of this technological approach was further confirmed by the characterization of a saturable [14C]taurine uptake in JAR cells. Taurine transport was of high affinity with a Km of 10.2+/-1.7 microM and fully inhibited by ALX-5407 (IC50=522 +/-83 nM). The developed assay is homogenous, rapid, versatile and amenable to automation for the discovery of new neurotransmitter transporter inhibitors.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Cloretos/farmacologia , Glicina/metabolismo , Contagem de Cintilação/métodos , Sódio/farmacologia , Sistemas de Transporte de Aminoácidos Neutros/genética , Radioisótopos de Carbono , Contagem de Células , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica , Glicina/antagonistas & inibidores , Glicina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Glicina , Humanos , Gravidez , Taurina/metabolismo , Fatores de Tempo
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