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1.
Neuropsychopharmacology ; 41(2): 598-610, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26108886

RESUMO

Schizophrenia patients exhibit deficits in signaling of the M1 subtype of muscarinic acetylcholine receptor (mAChR) in the prefrontal cortex (PFC) and also display impaired cortical long-term depression (LTD). We report that selective activation of the M1 mAChR subtype induces LTD in PFC and that this response is completely lost after repeated administration of phencyclidine (PCP), a mouse model of schizophrenia. Furthermore, discovery of a novel, systemically active M1 positive allosteric modulator (PAM), VU0453595, allowed us to evaluate the impact of selective potentiation of M1 on induction of LTD and behavioral deficits in PCP-treated mice. Interestingly, VU0453595 fully restored impaired LTD as well as deficits in cognitive function and social interaction in these mice. These results provide critical new insights into synaptic changes that may contribute to behavioral deficits in this mouse model and support a role for selective M1 PAMs as a novel approach for the treatment of schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Piridinas/farmacologia , Pirróis/farmacologia , Receptor Muscarínico M1/metabolismo , Esquizofrenia/tratamento farmacológico , Animais , Cognição/fisiologia , Modelos Animais de Doenças , Depressão Sináptica de Longo Prazo/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Patch-Clamp , Fenciclidina , Receptor Muscarínico M1/genética , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Comportamento Social
2.
ACS Chem Neurosci ; 6(10): 1683-95, 2015 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-26176846

RESUMO

The M1 muscarinic acetylcholine receptor (mAChR) subtype has been implicated in the underlying mechanisms of learning and memory and represents an important potential pharmacotherapeutic target for the cognitive impairments observed in neuropsychiatric disorders such as schizophrenia. Patients with schizophrenia show impairments in top-down processing involving conflict between sensory-driven and goal-oriented processes that can be modeled in preclinical studies using touchscreen-based cognition tasks. The present studies used a touchscreen visual pairwise discrimination task in which mice discriminated between a less salient and a more salient stimulus to assess the influence of the M1 mAChR on top-down processing. M1 mAChR knockout (M1 KO) mice showed a slower rate of learning, evidenced by slower increases in accuracy over 12 consecutive days, and required more days to acquire (achieve 80% accuracy) this discrimination task compared to wild-type mice. In addition, the M1 positive allosteric modulator BQCA enhanced the rate of learning this discrimination in wild-type, but not in M1 KO, mice when BQCA was administered daily prior to testing over 12 consecutive days. Importantly, in discriminations between stimuli of equal salience, M1 KO mice did not show impaired acquisition and BQCA did not affect the rate of learning or acquisition in wild-type mice. These studies are the first to demonstrate performance deficits in M1 KO mice using touchscreen cognitive assessments and enhanced rate of learning and acquisition in wild-type mice through M1 mAChR potentiation when the touchscreen discrimination task involves top-down processing. Taken together, these findings provide further support for M1 potentiation as a potential treatment for the cognitive symptoms associated with schizophrenia.


Assuntos
Colinérgicos/uso terapêutico , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/genética , Discriminação Psicológica/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Receptor Muscarínico M1/metabolismo , Análise de Variância , Animais , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estimulação Luminosa , Quinolonas/farmacologia , Quinolonas/uso terapêutico , RNA Mensageiro , Receptor Muscarínico M1/genética , Esquema de Reforço , Reforço Psicológico , Tato/fisiologia
3.
Oncogene ; 33(25): 3298-306, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-23912460

RESUMO

Despite the progress made in targeted anticancer therapies in recent years, challenges remain. The identification of new potential targets will ensure that the arsenal of cancer therapies continues to expand. FAM83B was recently discovered in a forward genetic screen for novel oncogenes that drive human mammary epithelial cell (HMEC) transformation. We report here that elevated FAM83B expression increases Phospholipase D (PLD) activity, and that suppression of PLD1 activity prevents FAM83B-mediated transformation. The increased PLD activity is engaged by hyperactivation of epidermal growth factor receptor (EGFR), which is regulated by an interaction involving FAM83B and EGFR. Preventing the FAM83B/EGFR interaction by site-directed mutation of lysine 230 of FAM83B suppressed PLD activity and MAPK signaling. Furthermore, ablation of FAM83B expression from breast cancer cells inhibited EGFR phosphorylation and suppressed cell proliferation. We propose that understanding the mechanism of FAM83B-mediated transformation will provide a foundation for future therapies aimed at targeting its function as an intermediary in EGFR, MAPK and mTOR activation.


Assuntos
Receptores ErbB/metabolismo , Proteínas de Neoplasias/metabolismo , Oncogenes/genética , Fosfolipase D/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Processos de Crescimento Celular/fisiologia , Linhagem Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ativação Enzimática , Células Epiteliais/metabolismo , Receptores ErbB/genética , Feminino , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas de Neoplasias/genética , Fosfolipase D/genética , Fosforilação , Transdução de Sinais
4.
J Pharmacol Exp Ther ; 347(2): 438-57, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23965381

RESUMO

Impaired transmission through glutamatergic circuits has been postulated to play a role in the underlying pathophysiology of schizophrenia. Furthermore, inhibition of the N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors (NMDAR) induces a syndrome that recapitulates many of the symptoms observed in patients with schizophrenia. Selective activation of metabotropic glutamate receptor subtype 5 (mGlu5) may provide a novel therapeutic approach for treatment of symptoms associated with schizophrenia through facilitation of transmission through central glutamatergic circuits. Here, we describe the characterization of two novel N-aryl piperazine mGlu5 positive allosteric modulators (PAMs): 2-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)benzonitrile (VU0364289) and 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone (DPFE). VU0364289 and DPFE induced robust leftward shifts in the glutamate concentration-response curves for Ca(2+) mobilization and extracellular signal-regulated kinases 1 and 2 phosphorylation. Both PAMs displayed micromolar affinity for the common mGlu5 allosteric binding site and high selectivity for mGlu5. VU0364289 and DPFE possessed suitable pharmacokinetic properties for dosing in vivo and produced robust dose-related effects in reversing amphetamine-induced hyperlocomotion, a preclinical model predictive of antipsychotic-like activity. In addition, DPFE enhanced acquisition of contextual fear conditioning in rats and reversed behavioral deficits in a mouse model of NMDAR hypofunction. In contrast, DPFE had no effect on reversing apomorphine-induced disruptions of prepulse inhibition of the acoustic startle reflex. These mGlu5 PAMs also increased monoamine levels in the prefrontal cortex, enhanced performance in a hippocampal-mediated memory task, and elicited changes in electroencephalogram dynamics commensurate with procognitive effects. Collectively, these data support and extend the role for the development of novel mGlu5 PAMs for the treatment of psychosis and cognitive deficits observed in individuals with schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Hipercinese/tratamento farmacológico , Memória de Curto Prazo/efeitos dos fármacos , Nootrópicos/farmacologia , Piperazinas/farmacologia , Receptor de Glutamato Metabotrópico 5/agonistas , Receptores de N-Metil-D-Aspartato/metabolismo , Regulação Alostérica , Animais , Antipsicóticos/química , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapêutico , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Humanos , Hipercinese/metabolismo , Hipercinese/psicologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Nootrópicos/química , Nootrópicos/farmacocinética , Nootrópicos/uso terapêutico , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/genética , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Transfecção
5.
Mol Pharmacol ; 83(4): 835-47, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23348500

RESUMO

Metabotropic glutamate receptor 5 (mGlu5) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease. Furthermore, mGlu5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term potentiation (LTP), which is thought to be involved in cognition. Multiple mGlu5-positive allosteric modulators (PAMs) have been developed from a variety of different scaffolds. Previous work has extensively characterized a common allosteric site on mGlu5, termed the MPEP (2-Methyl-6-(phenylethynyl)pyridine) binding site. However, one mGlu5 PAM, CPPHA (N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide), interacts with a separate allosteric site on mGlu5. Using cell-based assays and brain slice preparations, we characterized the interaction of a potent and efficacious mGlu5 PAM from the CPPHA series termed NCFP (N-(4-chloro-2-((4-fluoro-1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide). NCFP binds to the CPPHA site on mGlu5 and potentiates mGlu5-mediated responses in both recombinant and native systems. However, NCFP provides greater mGlu5 subtype selectivity than does CPPHA, making it more suitable for studies of effects on mGlu5 in CNS preparations. Of interest, NCFP does not potentiate responses involved in hippocampal synaptic plasticity (LTD/LTP), setting it apart from other previously characterized MPEP site PAMs. This suggests that although mGlu5 PAMs may have similar responses in some systems, they can induce differential effects on mGlu5-mediated physiologic responses in the CNS. Such stimulus bias by mGlu5 PAMs may complicate drug discovery efforts but would also allow for specifically tailored therapies, if pharmacological biases can be attributed to different therapeutic outcomes.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Benzamidas/metabolismo , Benzamidas/farmacologia , Ftalimidas/metabolismo , Ftalimidas/farmacologia , Receptores de Glutamato Metabotrópico/fisiologia , Transdução de Sinais/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Células Cultivadas , Feminino , Células HEK293 , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Transdução de Sinais/fisiologia
6.
Neuropharmacology ; 66: 330-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22705340

RESUMO

Absence epilepsy is generated by the cortico-thalamo-cortical network, which undergoes a finely tuned regulation by metabotropic glutamate (mGlu) receptors. We have shown previously that potentiation of mGlu1 receptors reduces spontaneous occurring spike and wave discharges (SWDs) in the WAG/Rij rat model of absence epilepsy, whereas activation of mGlu2/3 and mGlu4 receptors produces the opposite effect. Here, we have extended the study to mGlu5 receptors, which are known to be highly expressed within the cortico-thalamo-cortical network. We used presymptomatic and symptomatic WAG/Rij rats and aged-matched ACI rats. WAG/Rij rats showed a reduction in the mGlu5 receptor protein levels and in the mGlu5-receptor mediated stimulation of polyphosphoinositide hydrolysis in the ventrobasal thalamus, whereas the expression of mGlu5 receptors was increased in the somatosensory cortex. Interestingly, these changes preceded the onset of the epileptic phenotype, being already visible in pre-symptomatic WAG/Rij rats. SWDs in symptomatic WAG/Rij rats were not influenced by pharmacological blockade of mGlu5 receptors with MTEP (10 or 30 mg/kg, i.p.), but were significantly decreased by mGlu5 receptor potentiation with the novel enhancer, VU0360172 (3 or 10 mg/kg, s.c.), without affecting motor behaviour. The effect of VU0360172 was prevented by co-treatment with MTEP. These findings suggest that changes in mGlu5 receptors might lie at the core of the absence-seizure prone phenotype of WAG/Rij rats, and that mGlu5 receptor enhancers are potential candidates to the treatment of absence epilepsy. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.


Assuntos
Epilepsia Tipo Ausência/tratamento farmacológico , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Niacinamida/análogos & derivados , Receptores de Glutamato Metabotrópico/metabolismo , Fatores Etários , Animais , Ondas Encefálicas/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Eletroencefalografia/métodos , Epilepsia Tipo Ausência/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hidrólise , Masculino , Atividade Motora/efeitos dos fármacos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Fosfatos de Fosfatidilinositol/metabolismo , Piridinas/farmacologia , Ratos , Ratos Endogâmicos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Córtex Somatossensorial/metabolismo , Tiazóis/farmacologia , Núcleos Ventrais do Tálamo/metabolismo
7.
J Comb Chem ; 3(3): 312-8, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11350255

RESUMO

The synthesis and use of an alkylsilyl-tethered large (500-600 microm) polystyrene resin (1) are disclosed. An optimized Suzuki coupling of bromine-functionalized polystyrene and a silicon-functionalized alkylborane generates the silicon-substituted polystyrene 1 in large scale (>100 g). Resin loading is accomplished by activation as the silyl triflate, which can accommodate even sterically encumbered secondary alcohols and phenols. Treatment with HF/pyridine for linker cleavage is mild, efficient, and amenable to an automated, large-scale distribution system. This platform delivers, minimally, 50 nmol of each small molecule derived from a diversity-oriented, split-pool synthesis on a per bead basis for use in both forward and reverse chemical genetic assays. This technology satisfies many requirements of a one bead-one stock solution approach to chemical genetics.


Assuntos
Sistemas de Liberação de Medicamentos , Poliestirenos/síntese química , Alcinos/química , Bromo/química , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Desenho de Fármacos , Microesferas , Estrutura Molecular , Poliestirenos/química , Resinas Vegetais/química , Silanos/química , Relação Estrutura-Atividade
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