Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
J Pharmacol Exp Ther ; 336(1): 165-77, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20947638

RESUMO

The normalization of excessive glutamatergic neurotransmission through the activation of metabotropic glutamate 2 (mGlu2) receptors may have therapeutic potential in a variety of psychiatric disorders, including anxiety/depression and schizophrenia. Here, we characterize the pharmacological properties of N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a structurally novel, potent, and selective allosteric potentiator of human and rat mGlu2 receptors (EC(50) = 23 and 13 nM, respectively). THIIC produced anxiolytic-like efficacy in the rat stress-induced hyperthermia assay and the mouse stress-induced elevation of cerebellar cGMP and marble-burying assays. THIIC also produced robust activity in three assays that detect antidepressant-like activity, including the mouse forced-swim test, the rat differential reinforcement of low rate 72-s assay, and the rat dominant-submissive test, with a maximal response similar to that of imipramine. Effects of THIIC in the forced-swim test and marble burying were deleted in mGlu2 receptor null mice. Analysis of sleep electroencephalogram (EEG) showed that THIIC had a sleep-promoting profile with increased non-rapid eye movement (REM) and decreased REM sleep. THIIC also decreased the dark phase increase in extracellular histamine in the medial prefrontal cortex and decreased levels of the histamine metabolite tele-methylhistamine (t-MeHA) in rat cerebrospinal fluid. Collectively, these results indicate that the novel mGlu2-positive allosteric modulator THIIC has robust activity in models used to predict anxiolytic/antidepressant efficacy, substantiating, at least with this molecule, differentiation in the biological impact of mGlu2 potentiation versus mGlu2/3 orthosteric agonism. In addition, we provide evidence that sleep EEG and CSF t-MeHA might function as viable biomarker approaches to facilitate the translational development of THIIC and other mGlu2 potentiators.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Compostos de Benzil/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Imidazóis/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Linhagem Celular , Sistema Nervoso Central/química , Cerebelo/química , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Camundongos Knockout , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Ratos Wistar , Receptores de Glutamato Metabotrópico/fisiologia
2.
Neuropeptides ; 42(3): 367-75, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18329096

RESUMO

Neuropeptide Y (NPY) is an important central regulator of food consumption and energy expenditure via the hypothalamus. NPY containing neurons have a broad central distribution and are often colocalized with norepinephrine (NE). However, NPY deficient mice do not exhibit any substantial changes in food consumption, body weight or body composition when compared to wild type mice. Since NE and serotonin (5HT) are also important regulators of appetite and metabolism, we evaluated these systems in NPY deficient mice. Brain sections from NPY deficient and wild type mice were labeled with either (3)H-nisoxetine for the NE transporter (NET) or (3)H-citalopram for the 5HT transporter (SERT). Tyrosine hydroxylase expression was evaluated by radioimmunohistochemistry. Brain monoamines and metabolites were evaluated using HPLC. NPY deficient mice exhibited a substantial decrease in NET binding in most brain regions examined. NET binding was less than 50% of control binding in the cerebral cortex and subregions of the thalamus with the greatest decrease seen in the hypothalamus. In contrast, more modest and regionally variable changes were observed in the SERT binding with decreases in regions such as the accessory olfactory nucleus, glomerular layer of the olfactory bulb and the CA1 region of the hippocampus. Measurement of NE and 5HT content as well as the primary metabolites revealed increased NE turnover and decreased 5HT content in the hypothalamus. Therefore, developmental compensation by the NE and 5HT systems may contribute to the absence of a body weight phenotype in NPY deficient mice.


Assuntos
Monoaminas Biogênicas/metabolismo , Química Encefálica/genética , Neuropeptídeo Y/deficiência , Animais , Autorradiografia , Cromatografia Líquida de Alta Pressão , Citalopram , Fluoxetina/análogos & derivados , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Neuropeptídeo Y/genética , Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina , Tirosina 3-Mono-Oxigenase/biossíntese , Tirosina 3-Mono-Oxigenase/genética
3.
Neuropharmacology ; 128: 351-365, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29102759

RESUMO

DETQ, an allosteric potentiator of the dopamine D1 receptor, was tested in therapeutic models that were known to respond to D1 agonists. Because of a species difference in affinity for DETQ, all rodent experiments used transgenic mice expressing the human D1 receptor (hD1 mice). When given alone, DETQ reversed the locomotor depression caused by a low dose of reserpine. DETQ also acted synergistically with L-DOPA to reverse the strong hypokinesia seen with a higher dose of reserpine. These results indicate potential as both monotherapy and adjunct treatment in Parkinson's disease. DETQ markedly increased release of both acetylcholine and histamine in the prefrontal cortex, and increased levels of histamine metabolites in the striatum. In the hippocampus, the combination of DETQ and the cholinesterase inhibitor rivastigmine increased ACh to a greater degree than either agent alone. DETQ also increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB in the striatum, consistent with enhanced synaptic plasticity. In the Y-maze, DETQ increased arm entries but (unlike a D1 agonist) did not reduce spontaneous alternation between arms at high doses. DETQ enhanced wakefulness in EEG studies in hD1 mice and decreased immobility in the forced-swim test, a model for antidepressant-like activity. In rhesus monkeys, DETQ increased spontaneous eye-blink rate, a measure that is known to be depressed in Parkinson's disease. Together, these results provide support for potential utility of D1 potentiators in the treatment of several neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, cognitive impairment in schizophrenia, and major depressive disorder.


Assuntos
Doenças do Sistema Nervoso/metabolismo , Transtornos Psicóticos/metabolismo , Receptores de Dopamina D1/metabolismo , Animais , Antipsicóticos/uso terapêutico , Piscadela/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopaminérgicos/uso terapêutico , Isoquinolinas/uso terapêutico , Levodopa/uso terapêutico , Macaca mulatta , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças do Sistema Nervoso/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Transtornos Psicóticos/tratamento farmacológico , Receptores de Dopamina D1/genética , Reserpina/uso terapêutico , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos
4.
Schizophr Bull ; 33(6): 1291-7, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17660489

RESUMO

We have previously shown that the orexin-1 antagonist SB-334867 blocks the electrophysiological effects of haloperidol and olanzapine on the activity of A9 and A10 dopamine neurons. To evaluate if orexin-1 antagonists might block other effects of antipsychotic drugs in animals, we examined the effects of SB-334867 on behavioral, neurochemical, and neuroendocrine effects of antipsychotic drugs. Pretreatment with SB-334867 (0.01-10 mg/kg, intraperitoneal [IP]) significantly decreased the catalepsy produced by the administration of haloperidol (1 mg/kg, subcutaneous [SC]), risperidone (2 mg/kg, SC), and olanzapine (10 mg/kg, SC). Administration of SB-334467 also reversed catalepsy after it had been established in animals pretreated 2 hours earlier with haloperidol. However, pretreatment with SB-334867 (1-10 mg/kg, IP) did not block the decreases in exploratory locomotor activity produced by administration of haloperidol (0.1 mg/kg, SC) or risperidone (0.3 mg/kg, SC). In addition, pretreatment with SB-334867 (1-10 mg/kg, IP) neither blocked the increased levels of dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens or striatum nor the elevation in serum prolactin produced by administration of haloperidol (0.1 mg/kg, SC) and risperidone (1 mg/kg, SC). Administration of SB-334867 alone neither changed locomotor activity and DOPAC or prolactin levels nor produced catalepsy. These results show that orexin-1 antagonists block the catoleptogenic effects of antipsychotics but do not block other locomotor, neurochemical, or neuroendocrine effects of antipsychotics. Because catalepsy is thought to be a good predictor of extrapyramidal symptoms in humans, treatment with orexin-1 antagonists might decrease the occurrence or severity of antipsychotic treatment-emergent extrapyramidal symptoms in humans.


Assuntos
Antipsicóticos/antagonistas & inibidores , Doenças dos Gânglios da Base/tratamento farmacológico , Benzodiazepinas/antagonistas & inibidores , Benzoxazóis/farmacologia , Benzoxazóis/uso terapêutico , Catalepsia/tratamento farmacológico , Haloperidol/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Neuropeptídeos/antagonistas & inibidores , Risperidona/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Comportamento Animal/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Naftiridinas , Olanzapina , Orexinas , Prolactina/metabolismo , Ratos , Ratos Sprague-Dawley , Ureia/farmacologia , Ureia/uso terapêutico
5.
CNS Neurol Disord Drug Targets ; 14(5): 612-26, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25921737

RESUMO

Transmembrane AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor regulatory protein (TARP) γ-8 is an auxiliary protein associated with some AMPA receptors. Most strikingly, AMPA receptors associated with this TARP have a relatively high localization in the hippocampus. TARP γ-8 also modifies the pharmacology and trafficking of AMPA receptors. However, to date there is little understanding of the biological significance of this auxiliary protein. In the present set of studies we provide a characterization of the differential pharmacology and behavioral consequences of deletion of TARP γ-8 by comparing the wild type (WT) and γ-8 -/- (knock-out, KO) mouse. KO mice were mildly hyperactive in a locomotor arena but not in other environments compared to WT mice. Additionally, the KO mice demonstrated enhanced locomotor stimulatory effects of both d-amphetamine and phencyclidine. Marble-burying and digging behaviors were dramatically reduced in KO mice. In another assay that can detect anxiety-like phenotypes, the elevated plus maze, no differences were observed in overall movement or open arm entries. In the forced-swim assay, KO mice displayed decreases in immobility time like the antidepressant imipramine and the AMPA receptor potentiator, LY392098. In KO mice, the antidepressant-like effects of LY392098 were prevented whereas the effects of imipramine were unaffected. Convulsions were induced by pentylenetetrazole, N-methyl-D-aspartate, and by kainic acid. However, in KO mice, kainic acid produced less tonic convulsions and lethality. KO mice had reduced levels of norepinephrine in hippocampus and cerebellum but not in hypothalamus or prefrontal cortex, decreased levels of cAMP in hippocampus, and increased levels of acetylcholine in the hypothalamus and prefrontal cortex. KO mice displayed decreased turnover of dopamine and increased histamine turnover in multiple brain areas In contrast, serotonin and its metabolites were not significantly affected by deletion of the γ-8 protein. Of a large panel of plasma lipids, only two monoacylglycerols (1OG and 2OG) were marginally but nonsignificantly altered in WT vs KO mice. Overall, the data suggest genetic inactivation of this specific population of AMPA receptors results in modest changes in behavior characterized by a mild hyperactivity which is condition dependent and a marked reduction in digging and burying behaviors. Despite deletion of TARP γ-8, chemoconvulsants were still active. Consistent with their predicted pharmacological actions, the convulsant effects of kainate and the antidepressant-like effects of an AMPA receptor potentiator (both acting upon AMPA receptors) were reduced or absent in KO mice.


Assuntos
Temperatura Corporal/genética , Encéfalo/metabolismo , Canais de Cálcio/deficiência , Hipercinese/genética , Atividade Motora/genética , Receptores de AMPA/metabolismo , Acetilcolina/metabolismo , Anfetaminas/farmacologia , Animais , Monoaminas Biogênicas/metabolismo , Canais de Cálcio/genética , Estimulantes do Sistema Nervoso Central/farmacologia , AMP Cíclico/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/fisiologia , Histamina/metabolismo , Lipídeos/sangue , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Pentilenotetrazol , Fenciclidina/farmacologia , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/genética , Sulfonamidas/farmacologia , Natação/psicologia , Tiofenos/farmacologia , Fatores de Tempo
6.
Neuropharmacology ; 45(7): 935-44, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14573386

RESUMO

Compounds that block both serotonin (5-HT) and norepinephrine (NE) transporters have been proposed to have improved antidepressant efficacy. We compared the ability of four dual transporter inhibitors-chlorimipramine, duloxetine, milnacipran and venlafaxine-to block monoamine transporters in vitro and in vivo and increase extracellular monoamines in rat brain. Inhibition of radioligand binding to clonal human monoamine transporters in vitro and in vivo in rats was determined. Extracellular concentrations of 5-HT and NE in rat prefrontal cortex (PFC) were quantified using the microdialysis technique. All compounds blocked binding to human 5-HT and NE transporters, although chlorimipramine and venlafaxine had markedly greater affinity for 5-HT than NE transporters. In vivo, chlorimipramine and duloxetine potently blocked both transporters, milnacipran blocked both with lower potency and venlafaxine only blocked the 5-HT transporter. Chlorimipramine and duloxetine increased robustly and approximately equally monoamine extracellular concentrations. Milnacipran produced only small increases in NE, whereas venlafaxine increased 5-HT markedly at the lower doses and both monoamines at high doses. Thus, the dual transporter inhibitors blocked 5-HT and NE transporters in vitro and in vivo with varying potency. Chlorimipramine, duloxetine, and high dose venlafaxine acted as dual transporter inhibitors in rat PFC and increased extracellular concentrations of the monoamines, indicating functional dual transporter inhibition.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Monoaminas Biogênicas/metabolismo , Proteínas de Transporte/metabolismo , Espaço Extracelular/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Química Encefálica/efeitos dos fármacos , Clomipramina/farmacologia , Cicloexanóis/farmacologia , Ciclopropanos/farmacologia , Relação Dose-Resposta a Droga , Cloridrato de Duloxetina , Técnicas In Vitro , Masculino , Microdiálise , Milnaciprano , Norepinefrina/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Serotoninérgicos/farmacologia , Tiofenos/farmacologia , Cloridrato de Venlafaxina , alfa-Metiltirosina/farmacologia , p-Cloroanfetamina/farmacologia
7.
CNS Neurol Disord Drug Targets ; 12(4): 498-505, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23574162

RESUMO

Curcumin, the major constituent of the spice tumeric produces a plethora of biological actions that have translated in vivo into behavioral and neurochemical effects in rodents that are also produced by clinically-used antidepressants. The present study was designed to provide a systematic replication of prior behavioral, pharmacological, and neurochemical experiments. In particular, the ability of curcumin to engender anti-immobility effects in the mouse forced-swim assay was established. Although prior work had shown curcumin to function as an inhibitor of the monoamine metabolizing enzyme, monoamine oxidase (MAO), neither MAOA nor MAOB was inhibitied by curcumin in the present study. Curcumin had also been reported previously to function as a cannabinoid CB1 receptor inverse agonist/antagonist. However, in our hands, curcumin did not potently alter GTP-γ.-35S binding indicative of functional CB1 antagonism (Kb = 2080 nM). Moreover, curcumin was not able to prevent the hypothermic effects of the cannabinoid receptor agonist (-)-cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP 55,940). Nonetheless, the anti-immobility effects of curcumin did not occur in CB1 -/- mice. Finally, a broad array of protein receptors and enzymes were evaluated in vitro for their potential interaction with and/or functional engagement with curcumin. Of the more than 100 targets screened, curcumin had very low potency in most. Of those targets with appreciable activity, curcumin had affinities for the human cloned muscarinic receptor subtypes (Ki = 1.3-3.1 uM). Moreover, the plasma and brain levels of curcumin at behaviorally-active doses were below quantitative limits. Given these findings, it is concluded that the prominent antidepressant-like behavioral effects of curcumin, replicated here and in multiple acute and chronic rodent models detailed in the literature, are the result of as yet undisclosed mechanisms of action. The scientific and patient communities await the full scale clinical evaluation of a sufficiently bioavailable curcumin analog in major depressive disorder.


Assuntos
Antidepressivos/uso terapêutico , Curcumina/uso terapêutico , Depressão/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Curcumina/farmacologia , Cicloexanóis/farmacologia , Depressão/sangue , Depressão/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Imunossupressores/farmacologia , Masculino , Camundongos , Camundongos Knockout , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Receptor CB1 de Canabinoide/deficiência , Receptor CB1 de Canabinoide/metabolismo , Receptores de Amina Biogênica/metabolismo , Natação/psicologia
8.
ACS Med Chem Lett ; 4(6): 560-4, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900709

RESUMO

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.

9.
Bioorg Med Chem Lett ; 16(7): 2022-5, 2006 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-16413778

RESUMO

A novel series of tertiary alcohol containing 2-substituted benzyl morpholines have been discovered as potent and selective inhibitors of the norepinephrine transporter. Efficient synthetic routes were developed featuring a highly diastereoselective nucleophilic addition of benzyl Grignard reagents to enantiopure (4-benzylmorpholin-2-yl)phenylmethanone (11) as the key synthetic step. In vitro binding affinity for the norepinephrine, dopamine and serotonin transporters and in vivo examination of a select compound (16) in a pharmacodynamic animal model for norepinephrine reuptake inhibition are presented.


Assuntos
Álcoois/química , Morfolinas/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Cristalografia por Raios X , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Morfolinas/química
10.
Bioorg Med Chem Lett ; 16(9): 2347-51, 2006 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-16298130

RESUMO

A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT1A receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demonstrated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the initial acute activation of 5-HT1A somatodendritic autoreceptors.


Assuntos
Antidepressivos/farmacologia , Piperidinas/farmacologia , Propanóis/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Animais , Antidepressivos/administração & dosagem , Antidepressivos/química , Encéfalo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Técnicas In Vitro , Masculino , Conformação Molecular , Piperidinas/administração & dosagem , Piperidinas/química , Propanóis/administração & dosagem , Propanóis/química , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/química , Estereoisomerismo , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA