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1.
Skelet Muscle ; 13(1): 19, 2023 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-37980539

RESUMO

BACKGROUND: The lack of functional dystrophin protein in Duchenne muscular dystrophy (DMD) causes chronic skeletal muscle inflammation and degeneration. Therefore, the restoration of functional dystrophin levels is a fundamental approach for DMD therapy. Electrical impedance myography (EIM) is an emerging tool that provides noninvasive monitoring of muscle conditions and has been suggested as a treatment response biomarker in diverse indications. Although magnetic resonance imaging (MRI) of skeletal muscles has become a standard measurement in clinical trials for DMD, EIM offers distinct advantages, such as portability, user-friendliness, and reduced cost, allowing for remote monitoring of disease progression or response to therapy. To investigate the potential of EIM as a biomarker for DMD, we compared longitudinal EIM data with MRI/histopathological data from an X-linked muscular dystrophy (mdx) mouse model of DMD. In addition, we investigated whether EIM could detect dystrophin-related changes in muscles using antisense-mediated exon skipping in mdx mice. METHODS: The MRI data for muscle T2, the magnetic resonance spectroscopy (MRS) data for fat fraction, and three EIM parameters with histopathology were longitudinally obtained from the hindlimb muscles of wild-type (WT) and mdx mice. In the EIM study, a cell-penetrating peptide (Pip9b2) conjugated antisense phosphorodiamidate morpholino oligomer (PPMO), designed to induce exon-skipping and restore functional dystrophin production, was administered intravenously to mdx mice. RESULTS: MRI imaging in mdx mice showed higher T2 intensity at 6 weeks of age in hindlimb muscles compared to WT mice, which decreased at ≥ 9 weeks of age. In contrast, EIM reactance began to decline at 12 weeks of age, with peak reduction at 18 weeks of age in mdx mice. This decline was associated with myofiber atrophy and connective tissue infiltration in the skeletal muscles. Repeated dosing of PPMO (10 mg/kg, 4 times every 2 weeks) in mdx mice led to an increase in muscular dystrophin protein and reversed the decrease in EIM reactance. CONCLUSIONS: These findings suggest that muscle T2 MRI is sensitive to the early inflammatory response associated with dystrophin deficiency, whereas EIM provides a valuable biomarker for the noninvasive monitoring of subsequent changes in skeletal muscle composition. Furthermore, EIM reactance has the potential to monitor dystrophin-deficient muscle abnormalities and their recovery in response to antisense-mediated exon skipping.


Assuntos
Distrofina , Distrofia Muscular de Duchenne , Camundongos , Animais , Distrofina/genética , Distrofina/metabolismo , Camundongos Endogâmicos mdx , Impedância Elétrica , Camundongos Endogâmicos C57BL , Distrofia Muscular de Duchenne/diagnóstico por imagem , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Músculo Esquelético/metabolismo , Morfolinos/farmacologia , Morfolinos/uso terapêutico , Miografia , Biomarcadores
2.
Bioorg Med Chem ; 28(13): 115489, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32482533

RESUMO

Here, we present the design, synthesis, and SAR of dual orexin 1 and 2 receptor antagonists, which were optimized by balancing the antagonistic activity for orexin receptors and lipophilicity. Based on the prototype compound 1, ring construction and the insertion of an additional heteroatom into the resulting ring led to the discovery of orexin 1 and 2 receptor antagonists, which were 3-benzoyl-1,3-oxazinane derivatives. Within these derivatives, (-)-3h enabled a high dual orexin receptor antagonistic activity and a low lipophilicity. Compound (-)-3h exhibited potent sleep-promoting effects at a po dose of 1 mg/kg in a rat polysomnogram study, and optimal PK properties with a rapid Tmax and short half-lives in rats and dogs were observed, indicating a predicted human half-life of 0.9-2.0 h. Thus, (-)-3h (ORN0829; investigation code name, TS-142) was selected as a viable candidate and is currently in clinical development for the treatment of insomnia.


Assuntos
Antagonistas dos Receptores de Orexina/síntese química , Receptores de Orexina/metabolismo , Orexinas/química , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Masculino , Estrutura Molecular , Antagonistas dos Receptores de Orexina/farmacocinética , Orexinas/farmacocinética , Ratos Wistar , Sono/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
3.
Artigo em Inglês | MEDLINE | ID: mdl-26386976

RESUMO

A bioanalytical strategy for the simple and accurate determination of endogenous substances in a variety of biological matrices using liquid chromatography-tandem mass spectrometry is described. The robust method described here uses two stable isotope-labeled compounds as a surrogate analyte and an internal standard to construct calibration curves with authentic matrices that can be applied to determine N-acetyl-l-aspartyl-l-glutamic acid (NAAG) levels in rat brain, plasma, and cerebrospinal fluid (CSF) using a simple extraction and with a short analysis time of 4min. The validated lower limits of quantification were 1.00nmol/g for brain and 0.0100nmol/mL for plasma and CSF. Using this method, regional differences in NAAG levels in the brain as well as plasma and CSF levels that were much lower than those in the brain were successfully confirmed in treatment-naïve rats. Moreover, after the rats were treated with the intraventricular administration of a NAAG peptidase inhibitor, the NAAG levels increased rapidly and dramatically in the CSF and slightly in the plasma in a time-dependent manner, while the brain levels were not affected. Thus, the procedure described here was easily applied to the determination of NAAG in different matrices in the same manner as that used for xenobiotics, and this method would also be easily applicable to the accurate measurement of endogenous substances in a variety of biological matrices.


Assuntos
Química Encefálica , Cromatografia Líquida/métodos , Dipeptídeos/sangue , Dipeptídeos/líquido cefalorraquidiano , Espectrometria de Massas em Tandem/métodos , Animais , Masculino , Plasma/química , Ratos , Ratos Sprague-Dawley
4.
J Pharmacol Sci ; 127(3): 352-61, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25837934

RESUMO

Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. The stimulation of metabotropic glutamate (mGlu) 2 receptor has been shown to be effective in a number of animal models of schizophrenia. In this study, we investigated the antipsychotic profiles of (2S)-5-methyl-2-{[4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]methyl}-2,3-dihydroimidazo[2,1-b][1,3]oxazole-6-carboxamide (TASP0443294), a newly synthesized positive allosteric modulator of the mGlu2 receptor. TASP0443294 potentiated the response of human mGlu2 and rat mGlu2 receptors to glutamate with EC50 values of 277 and 149 nM, respectively, without affecting the glutamate response of human mGlu3 receptor. TASP0443294 was distributed in the brain and cerebrospinal fluid after peroral administration in rats. The peroral administration of TASP0443294 inhibited methamphetamine-induced hyperlocomotion in rats, which was attenuated by an mGlu2/3 receptor antagonist, and improved social memory impairment induced by 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) in rats. Furthermore, TASP0443294 reduced the ketamine-induced basal gamma hyperactivity in the prefrontal cortex and suppressed rapid eye movement (REM) sleep in rats. These findings indicate that TASP0443294 is an mGlu2 receptor positive allosteric modulator with antipsychotic activity, and that the suppression of aberrant gamma oscillations and REM sleep could be considered as neurophysiological biomarkers for TASP0443294.


Assuntos
Antipsicóticos/farmacologia , Imidazóis/farmacologia , Oxazóis/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Administração Oral , Regulação Alostérica/efeitos dos fármacos , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Células Cultivadas , Modelos Animais de Doenças , Eletroencefalografia/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Masculino , Atividade Motora/efeitos dos fármacos , Oxazóis/administração & dosagem , Oxazóis/farmacocinética , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Wistar , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Sono REM/efeitos dos fármacos , Estimulação Química
5.
J Pharmacol Exp Ther ; 351(3): 642-53, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25277141

RESUMO

Excess glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia, and the activation of metabotropic glutamate 2 (mGlu2) receptor may exert antipsychotic effects by normalizing glutamate transmission. In the present study, we investigated the neurophysiologic and antipsychotic profiles of TASP0433864 [(2S)-2-[(4-tert-butylphenoxy)methyl]-5-methyl-2,3-dihydroimidazo[2,1-b][1,3]oxazole-6-carboxamide], a newly synthesized positive allosteric modulator (PAM) of mGlu2 receptor. TASP0433864 exhibited PAM activity at human and rat mGlu2 receptors with EC50 values of 199 and 206 nM, respectively, without exerting agonist activity at rat mGlu2 receptor. TASP0433864 produced a leftward and upward shift in the concentration-response curve of glutamate-increased guanosine 5'-O-(3-[(35)S]thio)triphosphate binding to mGlu2 receptor. In contrast, TASP0433864 had negligible activities for other mGlu receptors, including mGlu3 receptor, and did not have any affinity for other receptors or transporters. In hippocampal slices, TASP0433864 potentiated an inhibitory effect of DCG-IV [(2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl)glycine], a mGlu2/3 receptor agonist, on the field excitatory postsynaptic potentials in the dentate gyrus, indicating that TASP0433864 potentiates the mGlu2 receptor-mediated presynaptic inhibition of glutamate release. Moreover, TASP0433864 inhibited both MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate]- and ketamine-increased cortical γ band oscillation in the rat cortical electroencephalogram, which have been considered to reflect the excess activation of cortical pyramidal neurons. The inhibitory effect of TASP0433864 on cortical activation was also observed in the mouse 2-deoxy-glucose uptake study. In a behavioral study, TASP0433864 significantly inhibited both ketamine- and methamphetamine-increased locomotor activities in mice and rats, respectively. Collectively, these findings indicate that TASP0433864 is a selective mGlu2 receptor PAM with antipsychotic activity, and the attenuation of excess glutamatergic neurotransmission may be involved in the action of TASP0433864.


Assuntos
Antipsicóticos/química , Antipsicóticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Oxazóis/química , Oxazóis/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/fisiologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Técnicas de Cultura de Órgãos , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar
6.
Neuropharmacology ; 85: 384-96, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24907590

RESUMO

Schizophrenic patients have been shown to exhibit abnormal cortical gamma band oscillation (GBO), which is thought to be related to the symptoms of schizophrenia, including cognitive impairment. Recently, non-competitive NMDA receptor (NMDAr) antagonists such as MK-801 and ketamine have been reported to increase the basal GBO power in rat cortical electroencephalograms. However, the mechanisms underlying the increase in basal GBO power induced by non-competitive NMDAr antagonists remain unclear. In the present study, we characterized the non-competitive NMDAr antagonists-increased GBO (30-80 Hz) power. MK-801 (0.05-0.2 mg/kg) increased the GBO power, exhibiting an inverted U-shape dose-response curve; at higher doses (0.3-1 mg/kg), the increase in GBO was reversed. The GBO power was closely correlated with the high-frequency oscillation (130-180 Hz) power following MK-801 administration, while the GBO power was inversely correlated with the increase in delta oscillation (0.5-4 Hz) power at higher doses. PCP (1.25-10 mg/kg) and ketamine (2.5-30 mg/kg) also exhibited the inverted U-shape dose-responses for the basal GBO power similar to MK-801. Interestingly, memantine (10-30 mg/kg) dose-dependently and potently increased the GBO power without remarkably affecting the other frequency band. In contrast, other psychotomimetics, such as methamphetamine (1-10 mg/kg) and DOI (0.5-2 mg/kg), did not induce noticeable changes in the basal GBO power even at doses that induce abnormal behaviors, indicating that the increase in GBO power induced by NMDAr antagonists is not necessarily attributed to psychotomimetic effects. In conclusion, the basal GBO power increase in response to non-competitive NMDAr antagonists may reflect the cortical hyperglutamatergic state through GABAergic disinhibition.


Assuntos
Encéfalo/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ritmo Gama/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Anfetaminas/farmacologia , Animais , Encéfalo/fisiologia , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Eletrodos Implantados , Eletroencefalografia , Ritmo Gama/fisiologia , Ketamina/farmacologia , Masculino , Memantina/farmacologia , Metanfetamina/farmacologia , Fenciclidina/farmacologia , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo
7.
Neurosci Lett ; 567: 30-4, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24680852

RESUMO

Abnormalities in electroencephalogram gamma oscillations have been implicated in schizophrenic symptoms. N-methyl-d-aspartate (NMDA) receptor antagonists produce behavioral abnormalities that are similar to the symptoms of schizophrenia, including social and cognitive impairment, and also increase the power of spontaneous gamma oscillations in the frontal cortex in rodents. Both mGlu2/3 receptor agonists and mGlu1 receptor antagonists reportedly improve behavioral abnormalities elicited by NMDA receptor antagonists in rodents. The present study evaluated the effects of an mGlu2/3 receptor agonist and an mGlu1 receptor antagonist on aberrant basal gamma oscillations elicited by an NMDA receptor antagonist, ketamine, in the rat frontal cortex. Ketamine increased spontaneous cortical gamma oscillations. Pretreatment with an mGlu2/3 receptor agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), or an mGlu1 receptor antagonist, (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685), reduced the ketamine-induced basal gamma hyperactivity. These findings indicate that the stimulation of mGlu2/3 receptors and the inhibition of mGlu1 receptors reverse aberrant gamma oscillations, and these effects may partially explain the antipsychotic-like properties of mGlu2/3 receptor agonists and mGlu1 receptor antagonists.


Assuntos
Lobo Frontal/efeitos dos fármacos , Ketamina/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Aminoácidos/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Eletroencefalografia , Lobo Frontal/fisiologia , Masculino , Quinolinas/farmacologia , Ratos Sprague-Dawley
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