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1.
J Neurosci ; 43(3): 501-521, 2023 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-36639889

RESUMO

The most common genetic risk factor for Parkinson's disease (PD) is heterozygous mutations GBA1, which encodes for the lysosomal enzyme, glucocerebrosidase. Reduced glucocerebrosidase activity associates with an accumulation of abnormal α-synuclein (α-syn) called Lewy pathology, which characterizes PD. PD patients heterozygous for the neuronotypic GBA1L444P mutation (GBA1+/L444P) have a 5.6-fold increased risk of cognitive impairments. In this study, we used GBA1+/L444P mice of either sex to determine its effects on lipid metabolism, expression of synaptic proteins, behavior, and α-syn inclusion formation. At 3 months of age, GBA1+/L444P mice demonstrated impaired contextual fear conditioning, and increased motor activity. Hippocampal levels of vGLUT1 were selectively reduced in GBA1+/L444P mice. We show, using mass spectrometry, that GBA1L444P expression increased levels of glucosylsphingosine, but not glucosylceramide, in the brains and serum of GBA1+/L444P mice. Templated induction of α-syn pathology in mice showed an increase in α-syn inclusion formation in the hippocampus of GBA1+/L444P mice compared with GBA1+/+ mice, but not in the cortex, or substantia nigra pars compacta. Pathologic α-syn reduced SNc dopamine neurons by 50% in both GBA1+/+ and GBA1+/L444P mice. Treatment with a GlcCer synthase inhibitor did not affect abundance of α-syn inclusions in the hippocampus or rescue dopamine neuron loss. Overall, these data suggest the importance of evaluating the contribution of elevated glucosylsphingosine to PD phenotypes. Further, our data suggest that expression of neuronotypic GBA1L444P may cause defects in the hippocampus, which may be a mechanism by which cognitive decline is more prevalent in individuals with GBA1-PD.SIGNIFICANCE STATEMENT Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are both pathologically characterized by abnormal α-synuclein (α-syn). Mutant GBA1 is a risk factor for both PD and DLB. Our data show the expression of neuronotypic GBA1L444P impairs behaviors related to hippocampal function, reduces expression of a hippocampal excitatory synaptic protein, and that the hippocampus is more susceptible to α-syn inclusion formation. Further, our data strengthen support for the importance of evaluating the contribution of glucosylsphingosine to PD phenotypes. These outcomes suggest potential mechanisms by which GBA1L444P contributes to the cognitive symptoms clinically observed in PD and DLB. Our findings also highlight the importance of glucosylsphingosine as a relevant biomarker for future therapeutics.


Assuntos
Glucosilceramidase , Doença de Parkinson , Sinucleinopatias , alfa-Sinucleína , Animais , Camundongos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Hipocampo/metabolismo , Mutação/genética , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Sinucleinopatias/patologia
2.
J Lipid Res ; 63(6): 100218, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35489416

RESUMO

A major challenge of lipidomics is to determine and quantify the precise content of complex lipidomes to the exact lipid molecular species. Often, multiple methods are needed to achieve sufficient lipidomic coverage to make these determinations. Multiplexed targeted assays offer a practical alternative to enable quantitative lipidomics amenable to quality control standards within a scalable platform. Herein, we developed a multiplexed normal phase liquid chromatography-hydrophilic interaction chromatography multiple reaction monitoring method that quantifies lipid molecular species across over 20 lipid classes spanning wide polarities in a single 20-min run. Analytical challenges such as in-source fragmentation, isomer separations, and concentration dynamics were addressed to ensure confidence in selectivity, quantification, and reproducibility. Utilizing multiple MS/MS product ions per lipid species not only improved the confidence of lipid identification but also enabled the determination of relative abundances of positional isomers in samples. Lipid class-based calibration curves were applied to interpolate lipid concentrations and guide sample dilution. Analytical validation was performed following FDA Bioanalytical Method Validation Guidance for Industry. We report repeatable and robust quantitation of 900 lipid species measured in NIST-SRM-1950 plasma, with over 700 lipids achieving inter-assay variability below 25%. To demonstrate proof of concept for biomarker discovery, we analyzed plasma from mice treated with a glucosylceramide synthase inhibitor, benzoxazole 1. We observed expected reductions in glucosylceramide levels in treated animals but, more notably, identified novel lipid biomarker candidates from the plasma lipidome. These data highlight the utility of this qualified lipidomic platform for enabling biological discovery.


Assuntos
Lipidômica , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida , Lipídeos , Camundongos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
3.
Neurobiol Dis ; 159: 105507, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34509608

RESUMO

Mutations in the lysosomal enzyme glucocerebrosidase (GCase, GBA1 gene) are the most common genetic risk factor for developing Parkinson's disease (PD). GCase metabolizes the glycosphingolipids glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Mutations in GBA1 reduce enzyme activity and the resulting accumulation of glycosphingolipids may contribute to the underlying pathology of PD, possibly via altering lysosomal function. While reduction of GCase activity exacerbates α-synuclein (α-syn) aggregation, it has not been determined that this effect is the result of altered glycosphingolipid levels and lysosome function or some other effect of altering GCase. The glycosphingolipid GlcCer is synthesized by a single enzyme, glucosylceramide synthase (GCS), and small molecule inhibitors (GCSi) reduce cellular glycosphingolipid levels. In the present studies, we utilize a preformed fibril (PFF) rodent primary neuron in vitro model of α-syn pathology to investigate the relationship between glycosphingolipid levels, α-syn pathology, and lysosomal function. In primary cultures, pharmacological inhibition of GCase and D409V GBA1 mutation enhanced accumulation of glycosphingolipids and insoluble phosphorylated α-syn. Administration of a novel small molecule GCSi, benzoxazole 1 (BZ1), significantly decreased glycosphingolipid concentrations in rodent primary neurons and reduced α-syn pathology. BZ1 rescued lysosomal deficits associated with the D409V GBA1 mutation and α-syn PFF administration, and attenuated α-syn induced neurodegeneration of dopamine neurons. In vivo studies revealed BZ1 had pharmacological activity and reduced glycosphingolipids in the mouse brain to a similar extent observed in neuronal cultures. These data support the hypothesis that reduction of glycosphingolipids through GCS inhibition may impact progression of synucleinopathy and BZ1 is useful tool to further examine this important biology.


Assuntos
Benzoxazóis/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Glucosilceramidase/genética , Glucosiltransferases/antagonistas & inibidores , Glicoesfingolipídeos/metabolismo , Lisossomos/efeitos dos fármacos , Sinucleinopatias/metabolismo , alfa-Sinucleína/efeitos dos fármacos , Animais , Neurônios Dopaminérgicos/metabolismo , Técnicas In Vitro , Lisossomos/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Cultura Primária de Células , Agregados Proteicos , Ratos , Sinucleinopatias/genética , alfa-Sinucleína/metabolismo
4.
Bioorg Med Chem Lett ; 26(12): 2952-2956, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27133481

RESUMO

A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and clogP, were used to guide compound design and attempt to improve inhibitor pharmacokinetics. Incorporation of heterocyclic central rings provided improvements in physicochemical parameters but did not significantly reduce in vitro or in vivo clearance. Nevertheless, compound 11 was identified as a potent inhibitor with sufficient in vivo exposure to significantly affect the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), and indicate central COMT inhibition.


Assuntos
Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Compostos Heterocíclicos/farmacologia , Piridonas/farmacologia , Animais , Inibidores de Catecol O-Metiltransferase/síntese química , Inibidores de Catecol O-Metiltransferase/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Piridonas/síntese química , Piridonas/química , Ratos , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 26(1): 126-32, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26602277

RESUMO

Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer.


Assuntos
Descoberta de Drogas , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Esquizofrenia/tratamento farmacológico , Animais , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Macaca mulatta , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Ratos , Ratos Wistar , Esquizofrenia/enzimologia , Relação Estrutura-Atividade
6.
J Med Chem ; 66(2): 1157-1171, 2023 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-36624931

RESUMO

PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia.


Assuntos
Inibidores de Fosfodiesterase , Esquizofrenia , Humanos , Cristalografia por Raios X , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/química , Esquizofrenia/tratamento farmacológico , Relação Estrutura-Atividade
7.
ACS Med Chem Lett ; 14(2): 146-155, 2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36793422

RESUMO

Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson's disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS). Herein, we report the optimization of a bicyclic pyrazole amide GCS inhibitor discovered through HTS to low dose, oral, CNS penetrant, bicyclic pyrazole urea GCSi's with in vivo activity in mouse models and ex vivo activity in iPSC neuronal models of synucleinopathy and lysosomal dysfunction. This was accomplished through the judicious use of parallel medicinal chemistry, direct-to-biology screening, physics-based rationalization of transporter profiles, pharmacophore modeling, and use a novel metric: volume ligand efficiency.

8.
Bioorg Med Chem Lett ; 22(18): 5903-8, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22892116

RESUMO

We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. Lead compound THPP-1 exhibits nanomolar potencies, excellent pharmacokinetic properties, and a clean off-target profile. It displays in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing. It shows dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay. Further, THPP-1 displays significantly fewer preclinical adverse events in assays measuring prolactin secretion, catalepsy, and weight gain, in contrast to the typical and atypical antipsychotics haloperidol and olanzapine.


Assuntos
Descoberta de Drogas , Inibidores de Fosfodiesterase/uso terapêutico , Piridinas/farmacologia , Pirimidinas/farmacologia , Esquizofrenia/tratamento farmacológico , Administração Oral , Animais , GMP Cíclico/análise , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Piridinas/administração & dosagem , Piridinas/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Relação Estrutura-Atividade
9.
PLoS One ; 16(6): e0252325, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34106956

RESUMO

Multiple mutations have been described in the human GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase) that degrades glucosylceramide and is pivotal in glycosphingolipid substrate metabolism. Depletion of GCase, typically by homozygous mutations in GBA1, is linked to the lysosomal storage disorder Gaucher's disease (GD) and distinct or heterozygous mutations in GBA1 are associated with increased Parkinson's disease (PD) risk. While numerous genes have been linked to heritable PD, GBA1 mutations in aggregate are the single greatest risk factor for development of idiopathic PD. The importance of GCase in PD necessitates preclinical models in which to study GCase-related mechanisms and novel therapeutic approaches, as well as to elucidate the molecular mechanisms leading to enhanced PD risk in GBA1 mutation carriers. The aim of this study was to develop and characterize a novel GBA1 mouse model and to facilitate wide accessibility of the model with phenotypic data. Herein we describe the results of molecular, biochemical, histological, and behavioral phenotyping analyses in a GBA1 D409V knock-in (KI) mouse. This mouse model exhibited significantly decreased GCase activity in liver and brain, with substantial increases in glycosphingolipid substrates in the liver. While no changes in the number of dopamine neurons in the substantia nigra were noted, subtle changes in striatal neurotransmitters were observed in GBA1 D409V KI mice. Alpha-synuclein pathology and inflammation were not observed in the nigrostriatal system of this model. In summary, the GBA1 D409V KI mouse model provides an ideal model for studies aimed at pharmacodynamic assessments of potential therapies aiming to restore GCase.


Assuntos
Glucosilceramidase/metabolismo , Glicoesfingolipídeos/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Técnicas de Introdução de Genes , Glucosilceramidase/genética , Immunoblotting , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transtornos Parkinsonianos/enzimologia , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/metabolismo , Mutação Puntual/genética
10.
J Pharmacol Exp Ther ; 328(3): 921-30, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19088300

RESUMO

Multiple studies indicate that N-methyl-D-aspartate (NMDA) receptor hypofunction underlies some of the deficits associated with schizophrenia. One approach for improving NMDA receptor function is to enhance occupancy of the glycine modulatory site on the NMDA receptor by increasing the availability of the endogenous coagonists D-serine. Here, we characterized a novel D-amino acid oxidase (DAAO) inhibitor, compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and compared it with D-serine. Compound 8 is a moderately potent inhibitor of human (IC(50), 145 nM) and rat (IC(50), 114 nM) DAAO in vitro. In rats, compound 8 (200 mg/kg) decreased kidney DAAO activity by approximately 96% and brain DAAO activity by approximately 80%. This marked decrease in DAAO activity resulted in a significant (p < 0.001) elevation in both plasma (220% of control) and cerebrospinal fluid (CSF; 175% of control) D-serine concentration. However, compound 8 failed to significantly influence amphetamine-induced psychomotor activity, nucleus accumbens dopamine release, or an MK-801 (dizocilpine maleate)-induced deficit in novel object recognition in rats. In contrast, high doses of D-serine attenuated both amphetamine-induced psychomotor activity and dopamine release and also improved performance in novel object recognition. Behaviorally efficacious doses of D-serine (1280 mg/kg) increased CSF levels of D-serine 40-fold above that achieved by the maximal dose of compound 8. These findings demonstrate that pharmacological inhibition of DAAO significantly increases D-serine concentration in the periphery and central nervous system. However, acute inhibition of DAAO appears not to be sufficient to increase D-serine to concentrations required to produce antipsychotic and cognitive enhancing effects similar to those observed after administration of high doses of exogenous D-serine.


Assuntos
D-Aminoácido Oxidase/farmacologia , Pirróis/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Serina/farmacologia , Tiofenos/farmacologia , Idoso , Animais , Maleato de Dizocilpina/farmacologia , Habituação Psicofisiológica , Humanos , Masculino , Modelos Moleculares , Ratos , Ratos Wistar , Esquizofrenia/sangue , Esquizofrenia/líquido cefalorraquidiano , Serina/sangue , Serina/líquido cefalorraquidiano , Tiofenos/química
11.
Neuropharmacology ; 99: 256-63, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26044638

RESUMO

Phosphodiesterase 10A (PDE10A) has garnered attention as a potential therapeutic target for schizophrenia due to its prominent striatal expression and ability to modulate striatal signaling. The present study used the selective PDE10A inhibitor MP-10 and the dopamine D2 antagonist haloperidol to compare effects of PDE10A inhibition and dopamine D2 blockade on striatopallidal (D2) and striatonigral (D1) pathway activation. Our studies confirmed that administration of MP-10 significantly elevates expression of the immediate early genes (IEG) c-fos, egr-1, and arc in rat striatum. Furthermore, we demonstrated that MP-10 induced egr-1 expression was distributed evenly between enkephalin-containing D2-neurons and substance P-containing D1-neurons. In contrast, haloperidol (3 mg/kg) selectively activated egr-1 expression in enkephalin neurons. Co-administration of MP-10 and haloperidol (0.5 mg/kg) increased IEG expression to a greater extent than either compound alone. Similarly, in a rat catalepsy assay, administration of haloperidol (0.5 mg/kg) or MP-10 (3-30 mg/kg) did not produce cataleptic behavior when dosed alone, but co-administration of haloperidol with MP-10 (3 and 10 mg/kg) induced cataleptic behaviors. Interestingly, co-administration of haloperidol with a high dose of MP-10 (30 mg/kg) failed to produce cataleptic behavior. These findings are important for understanding the neural circuits involved in catalepsy and suggest that the behavioral effects produced by PDE10A inhibitors may be influenced by concomitant medication and the level of PDE10A inhibition achieved by the dose of the inhibitor.


Assuntos
Catalepsia/induzido quimicamente , Corpo Estriado/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Pirazóis/farmacologia , Quinolinas/farmacologia , Animais , Catalepsia/metabolismo , Corpo Estriado/metabolismo , Proteínas do Citoesqueleto/metabolismo , Relação Dose-Resposta a Droga , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Encefalinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Masculino , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Ratos Wistar , Receptores de Dopamina D2/metabolismo , Substância P/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo
12.
Neuropharmacology ; 64: 215-23, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22750078

RESUMO

Phosphodiesterase 10A (PDE10A) is a novel target for the treatment of schizophrenia that may address multiple symptomatic domains associated with this disorder. PDE10A is highly expressed in the brain and functions to metabolically inactivate the important second messengers cAMP and cGMP. Here we describe effects of a potent and orally bioavailable PDE10A inhibitor [2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl](imidazo[1,5-a]pyridin-1-yl)methanone] (THPP-1) on striatal signaling pathways, in behavioral tests that predict antipsychotic potential, and assays that measure episodic-like memory in rat and executive function in rhesus monkey. THPP-1 exhibits nanomolar potency on the PDE10A enzyme, demonstrates excellent pharmacokinetic properties in multiple preclinical animal species, and is selective for PDE10A over other PDE families of enzymes. THPP-1 significantly increased phosphorylation of proteins in the striatum involved in synaptic plasticity, including the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) GluR1 subunit, extracellular receptor kinase (ERK), and cAMP-response element binding protein (CREB). THPP-1 produced dose-dependent effects in preclinical assays predictive of antipsychotic activity including attenuation of MK-801-induced psychomotor activation and condition avoidance responding in rats. At similar plasma exposures, THPP-1 significantly increased object recognition memory in rat and attenuated a ketamine-induced deficit in the object retrieval detour task in rhesus monkey. These findings suggest that PDE10A inhibitors have the potential to impact multiple symptomatic domains of schizophrenia including positive symptoms and cognitive impairment. This article is part of a Special Issue entitled 'Cognitive Enhancers'.


Assuntos
Antipsicóticos/uso terapêutico , Transtornos Cognitivos/prevenção & controle , Terapia de Alvo Molecular , Nootrópicos/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Esquizofrenia/tratamento farmacológico , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/sangue , Antipsicóticos/farmacocinética , Comportamento Animal/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/enzimologia , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Função Executiva/efeitos dos fármacos , Macaca mulatta , Masculino , Memória Episódica , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/metabolismo , Nootrópicos/administração & dosagem , Nootrópicos/sangue , Nootrópicos/farmacocinética , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/sangue , Inibidores de Fosfodiesterase/farmacocinética , Diester Fosfórico Hidrolases/química , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Piridinas/administração & dosagem , Piridinas/sangue , Piridinas/farmacocinética , Piridinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Wistar , Esquizofrenia/sangue , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia
13.
ACS Chem Neurosci ; 3(2): 129-40, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22860182

RESUMO

Reduced dopamine neurotransmission in the prefrontal cortex has been implicated as causal for the negative symptoms and cognitive deficit associated with schizophrenia; thus, a compound which selectively enhances dopamine neurotransmission in the prefrontal cortex may have therapeutic potential. Inhibition of catechol-O-methyltransferase (COMT, EC 2.1.1.6) offers a unique advantage, since this enzyme is the primary mechanism for the elimination of dopamine in cortical areas. Since membrane bound COMT (MB-COMT) is the predominant isoform in human brain, a high throughput screen (HTS) to identify novel MB-COMT specific inhibitors was completed. Subsequent optimization led to the identification of novel, non-nitrocatechol COMT inhibitors, some of which interact specifically with MB-COMT. Compounds were characterized for in vitro efficacy versus human and rat MB and soluble (S)-COMT. Select compounds were administered to male Wistar rats, and ex vivo COMT activity, compound levels in plasma and cerebrospinal fluid (CSF), and CSF dopamine metabolite levels were determined as measures of preclinical efficacy. Finally, novel non-nitrocatechol COMT inhibitors displayed less potent uncoupling of the mitochondrial membrane potential (MMP) compared to tolcapone as well as nonhepatotoxic entacapone, thus mitigating the risk of hepatotoxicity.


Assuntos
Antipsicóticos/farmacocinética , Inibidores de Catecol O-Metiltransferase , Catecol O-Metiltransferase/metabolismo , Inibidores Enzimáticos/farmacologia , Animais , Antipsicóticos/síntese química , Benzofenonas/química , Benzofenonas/farmacologia , Biomarcadores , Western Blotting , Catecol O-Metiltransferase/isolamento & purificação , Membrana Celular/enzimologia , Membrana Celular/metabolismo , Dopamina/metabolismo , Inibidores Enzimáticos/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/isolamento & purificação , Isoenzimas/metabolismo , Masculino , Metaloproteinases da Matriz/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nitrofenóis/química , Nitrofenóis/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Proteínas Recombinantes/química , Esquizofrenia/tratamento farmacológico , Especificidade por Substrato , Tolcapona
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