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1.
J Craniofac Surg ; 30(7): 2102-2105, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31574784

RESUMO

OBJECTIVE: To explore the efficacy of nerve injury unit mode and conventional management mode for the treatment of patients with moderate or severe traumatic brain injury (TBI). METHODS: Eighty patients with TBI in our hospital from July 2016 to December 2017 were included as observation groups (Treated with injury unit mode). Eighty-three patients with TBI from January 2015 to June 2016 were included as control group (Treated with conventional management mode). The incidence of complications, satisfaction rate, Glasgow Coma Scale (GCS) scores, Barthel index (BI), National Institutes of Health Stroke Scale (NIHSS) scores and average length of hospital stay of 2 groups were compared. RESULTS: Observation group achieved lower incidence of complications, higher satisfaction rate, higher GCS scores, higher GOS prognosis scores, higher BI, lower NIHSS scores, and shorter average length of hospital stay compared with control group (P < 0.05). There were no significant differences in the average hospitalization cost between 2 groups (P > 0.05). CONCLUSION: For patients with TBI, the nerve injury unit mode can reduce the incidence of complications, improve patient satisfaction rate, shorten the hospitalization time, enhance the daily living ability, improve the patient's neurological function, improve the ability to return to society and have a significant role in promoting the rehabilitation of patients.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas Traumáticas/diagnóstico , Escala de Coma de Glasgow , Custos Hospitalares , Humanos , Tempo de Internação , Centros de Traumatologia
2.
Stroke ; 50(12): 3481-3487, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31570084

RESUMO

Background and Purpose- Early use of antiplatelet drugs within 24 hours after intravenous thrombolysis (IVT) has always been a confusing clinical problem. The purpose of this study was to assess the safety and efficacy of early low-dose tirofiban treatment in patients with early neurological deterioration (END) within the first 24 hours after IVT. Methods- This was a retrospective analysis of prospectively collected data of 1764 consecutive patients with acute ischemic stroke treated with IVT between January 2017 and September 2018. Patients with early neurological deterioration within the first 24 hours after IVT were treated with or without tirofiban. The safety outcomes included symptomatic intracranial hemorrhage, any ICH, severe systemic bleeding, and mortality. Efficacy outcomes included excellent (modified Rankin scale scores 0-1) and favorable (modified Rankin scale scores 0-2) 3-month functional outcomes. Results- Early neurological deterioration occurred in 278 (15.8%) patients. Of the 187 eligible patients, 121 (64.7%) were treated with tirofiban within the first 24 hours after IVT. Adjusted multivariate analysis showed that early tirofiban use was not associated with symptomatic intracranial hemorrhage (adjusted odds ratio [aOR], 1.05; 95% CI, 0.088-11.02; P=1.000), ICH (aOR, 1.13; 95% CI, 0.45-4.25; P=0.512), and mortality (aOR, 0.77; 95% CI, 0.19-2.27; P=0.875) but was significantly associated with excellent (aOR, 2.24; 95% CI, 1.16-3.94; P=0.027) and favorable (aOR, 2.31; 95% CI, 1.48-3.99; P=0.011) functional outcomes. Subgroup analyses suggested that early tirofiban-use efficacy is time dependent, being more effective in patients receiving tirofiban treatment earlier. Conclusions- Low-dose tirofiban use in patients with early neurological deterioration within the first 24 hours after IVT did not increase the risk of symptomatic intracranial hemorrhage, ICH, and mortality, it seems associated with neurological improvement at 3 months. Future randomized clinical trials will be needed to validate these results.

3.
Microcirculation ; 25(8): e12499, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30120860

RESUMO

BACKGROUND: LncRNA-FENDRR is a kind of endothelial genes critical for vascular development. Moreover, miR-126 and vascular endothelial growth factor A (VEGFA) are also involved in the physiological process of vascular endothelial cells. This study aimed to the underlying mechanism of FENDRR involving miR-126 and VEGFA in hypertensive intracerebral hemorrhage (HICH). METHODS: C57BL/6 mice were chosen to establish HICH model. The expression of FENDRR, miR-126, and VEGFA at mRNA level was determined by qRT-PCR. The protein expression of VEGFA was assessed using Western blot. RIP assay and RNA pull-down assay were used to the relationship between FENDRR and miR-126. Flow cytometry was used to analyze cell apoptosis. RESULTS: The levels of FENDRR and VEGFA were increased, and miR-126 expression was decreased in vascular endothelial cells (VECs) from the right brain of model mice and human brain microvascular endothelial cells (HBMECs) treated by thrombin. Overexpression of FENDRR promoted the apoptosis of HBMECs. FENDRR regulating VEGFA participated in HBMECs apoptosis through targeting miR-126. Downregulation of FENDRR was indicated to relieve the HICH in mice. CONCLUSIONS: FENDRR could promote the apoptosis of HBMECs via miR-126 regulating VEGFA in HICH.


Assuntos
Apoptose , Células Endoteliais/patologia , Hemorragia Intracraniana Hipertensiva/metabolismo , MicroRNAs/fisiologia , RNA Longo não Codificante/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Encéfalo/patologia , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/patologia
4.
ACS Chem Biol ; 13(8): 2033-2039, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-29767950

RESUMO

Benzodiazepines are clinically relevant drugs that bind to GABAA neurotransmitter receptors at the α+/γ2- interfaces and thereby enhance GABA-induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high-affinity site at GABAA receptors is controversially debated in the literature, and in silico studies led to discrepant binding mode hypotheses. In this study, computational docking of diazepam into α+/γ2- homology models suggested that a chiral methyl group, which is known to promote preferred binding to α5-containing GABAA receptors (position 3 of the seven-membered diazepine ring), could possibly provide experimental evidence that supports or contradicts the proposed binding modes. Thus, we investigated three pairs of R and S isomers of structurally different chemotypes, namely, diazepam, imidazobenzodiazepine, and triazolam derivatives. We used radioligand displacement studies as well as two-electrode voltage clamp electrophysiology in α1ß3γ2-, α2ß3γ2-, α3ß3γ2-, and α5ß3γ2-containing GABAA receptors to determine the ligand binding and functional activity of the three chemotypes. Interestingly, both imidazobenzodiazepine isomers displayed comparable binding affinities, while for the other two chemotypes, a discrepancy in binding affinities of the different isomers was observed. Specifically, the R isomers displayed a loss of binding, whereas the S isomers remained active. These findings are in accordance with the results of our in silico studies suggesting the usage of a different binding mode of imidazobenzodiazepines compared to those of the other two tested chemotypes. Hence, we conclude that different chemically related benzodiazepine ligands interact via distinct binding modes rather than by using a common binding mode.


Assuntos
Benzodiazepinas/química , Receptores de GABA-A/química , Triazóis/química , Animais , Sítios de Ligação , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Estereoisomerismo , Trítio
5.
Br J Pharmacol ; 169(2): 371-83, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23472852

RESUMO

BACKGROUND AND PURPOSE: GABAA receptors are the major inhibitory neurotransmitter receptors in the mammalian brain and the target of many clinically important drugs interacting with different binding sites. Recently, we demonstrated that CGS 9895 (2-(4-methoxyphenyl)-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) acts as a null modulator (antagonist) at the high affinity benzodiazepine binding site, but in addition elicits a strong enhancement of GABA-induced currents via a novel drug binding site at the extracellular α+ß- interface. Here, we investigated 32 structural analogues of CGS 9895 for their ability to mediate their effects via the α1+ß3- interface of GABAA receptors. EXPERIMENTAL APPROACH: GABAA receptors were expressed in Xenopus laevis oocytes and investigated by the two-electrode voltage clamp method. KEY RESULTS: We not only identified compounds with higher efficacy/potency than CGS 9895 for stimulating GABA-induced currents via the α1+ß3-binding site, but also discovered compounds acting as null modulators at this site. Most of the compounds also acted as null modulators via the benzodiazepine binding site of GABAA receptors. But some of the positive allosteric modulators or null modulators exclusively exerted their action via the α+ß- binding site. CONCLUSION AND IMPLICATIONS: Pyrazoloquinolinones and pyrazolopyridinones represent the first prototype of drug candidates mediating benzodiazepine like modulatory effects via the α+ß-interface of GABAA receptors. The discovery of null modulators acting as inhibitors of the plus modulators provides a highly useful tool for the discovery of additional classes of compounds that can modulate GABAA receptors via this site, which may lead to novel therapeutic principles.


Assuntos
Moduladores GABAérgicos/farmacologia , Pirazóis/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Regulação Alostérica , Animais , Sítios de Ligação , Feminino , Moduladores GABAérgicos/química , Oócitos , Técnicas de Patch-Clamp , Pirazóis/química , Relação Quantitativa Estrutura-Atividade , Receptores de GABA-A/metabolismo , Xenopus laevis
6.
Br J Pharmacol ; 169(2): 384-99, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23472935

RESUMO

BACKGROUND AND PURPOSE: GABAA receptors are the major inhibitory neurotransmitter receptors in the mammalian brain and the target of many clinically important drugs interacting with different binding sites. Recently, we demonstrated that CGS 9895 (2-(4-methoxyphenyl)-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) elicits a strong and subtype-dependent enhancement of GABA-induced currents via a novel drug-binding site at extracellular αx+ßy- (x = 1-6, y = 1-3) interfaces. Here, we investigated 16 structural analogues of CGS 9895 for their ability to modulate GABA-induced currents of various GABAA receptor subtypes. EXPERIMENTAL APPROACH: Recombinant GABAA receptor subtypes were expressed in Xenopus laevis oocytes and investigated by the two-electrode voltage clamp method. KEY RESULTS: Most of the compounds investigated were able to modulate GABA-induced currents of αß and αßγ receptors to a comparable extent, suggesting that the effect of these drugs is not dependent on the benzodiazepine site of GABAA receptors. Steric hindrance experiments demonstrated that these compounds exert their action predominantly via the αx+ßy- (x = 1-6, y = 1-3) interfaces. Whereas some compounds are unselectively modulating a broad range of receptor subtypes, other compounds feature remarkable functional selectivity for the α6ß3γ2 receptor, or behave as null modulators at some receptor subtypes investigated. CONCLUSION AND IMPLICATIONS: Pyrazoloquinolinones and pyrazolopyridinones represent the first prototypes of drugs exerting benzodiazepine-like modulatory effects via the α+ß- interface of GABAA receptors. The discovery of modulators with functional subtype selectivity at this class of binding sites provides a highly useful tool for the investigation of α6ß2/3γ2 receptor function, and may lead to novel therapeutic principles.


Assuntos
Moduladores GABAérgicos/farmacologia , Pirazóis/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Animais , Sítios de Ligação , Feminino , Humanos , Ligantes , Oócitos , Técnicas de Patch-Clamp , Pirazóis/química , Receptores de GABA-A/metabolismo , Xenopus laevis
7.
Eur J Pharmacol ; 703(1-3): 18-24, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23380687

RESUMO

Neocortical neurons mediate the sedative and anticonvulsant properties of benzodiazepines. These agents enhance synaptic inhibition via positive modulation of γ-aminobutyric acid (GABAA) receptors harboring α1-, α2-, α3- or α5-protein subunits. Benzodiazepine-sensitive GABAA receptors containing the α5-subunit are abundant in the neocortex, but their impact in controlling neuronal firing patterns is unknown. Here we studied how the discharge rates of cortical neurons are modified by a positive (SH-053-2'F-R-CH3) and a negative (L 655,708) α5-subunit-preferring allosteric modulator in comparison to diazepam, the classical non-selective benzodiazepine. Drug actions were characterized in slice cultures from wild-type and α5(H105R) knock-in mice by performing extracellular multi-unit-recordings. In knock-in mice, receptors containing the α5 subunit are insensitive to benzodiazepines. The non-selective positive allosteric modulator diazepam decreased the discharge rates of neocortical neurons during episodes of ongoing neuronal activity (up states). In contrast to diazepam, the α5-preferring positive modulator SH-053-2'F-R-CH3 accelerated action potential firing during up states. This promoting action was absent in slices from α5(H105R) mice, confirming that it is mediated by the α5-subunit. Consistent with these observations, the negative α5-selective modulator L 655,708 inhibited up state action potential activity in slices from wild-type mice. The opposing actions of diazepam and SH-053-2'F-R-CH3, which both enhance GABAA receptor function but differ in subtype-selectivity, uncovers contrasting roles of GABAA receptor subtypes in controlling the firing rates of cortical neurons. These findings may have important implications for the design of novel anaesthetic and anticonvulsant benzodiazepines displaying an improved efficacy and fewer side effects.


Assuntos
Diazepam/análogos & derivados , Agonistas de Receptores de GABA-A/farmacologia , Imidazóis/farmacologia , Neurônios/efeitos dos fármacos , Receptores de GABA-A/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Diazepam/farmacologia , Feminino , Técnicas In Vitro , Masculino , Camundongos , Camundongos Transgênicos , Neocórtex/citologia , Neurônios/fisiologia
8.
Psychopharmacology (Berl) ; 219(3): 897-908, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21833506

RESUMO

RATIONALE: Repeated activation of corticotropin-releasing factor (CRF) receptors is associated with increased anxiety and enhanced stress responsivity, which may be mediated via limbic GABAergic and glutamatergic transmission. OBJECTIVE: The present study investigated molecular and functional alterations in GABA(A) receptor (GABA(A)R) and metabotropic glutamate receptor (mGluR) responsivity in transgenic mice that chronically overexpress CRF. METHODS: CRF(1) receptor, GABA(A)R, and mGluR sensitivity were determined in CRF-overexpressing mice using the stress-induced hyperthermia (SIH) test. In addition, we measured mRNA expression levels of GABA(A)R α subunits and mGluRs in the amygdala and hypothalamus. RESULTS: CRF-overexpressing mice were less sensitive to the anxiolytic effects of the CRF(1) receptor antagonists CP154,526 and DMP695, the GABA(A)R α(3)-selective agonist TP003 (0-3 mg/kg) and the mGluR(2/3) agonist LY379268 (0-10 mg/kg) in the SIH test. The hypothermic effect of the non-selective GABA(A)R agonist diazepam (0-4 mg/kg) and the α(1)-subunit-selective GABA(A)R agonist zolpidem (0-10 mg/kg) was reduced in CRF-overexpressing mice. No genotype differences were found using the GABA(A)R α(5)-subunit preferential compound SH-053-2'F-R-CH(3) and mGluR(5) antagonists MPEP and MTEP. CRF-overexpressing mice showed decreased expression levels of GABA(A)R α(2) subunit and mGluR(3) mRNA levels in the amygdala, whereas these expression levels were increased in the hypothalamus. CRF-overexpressing mice also showed increased hypothalamic mRNA levels of α(1) and α(5) GABA(A)R subunits. CONCLUSIONS: We found that lifelong CRF overproduction is associated with altered gene expression and reduced functional sensitivity of discrete GABA(A) and mGluR receptor subtypes. These findings suggest that sustained over-activation of cerebral CRF receptors may contribute to the development of altered stress-related behavior via modulation of GABAergic and glutamatergic transmission.


Assuntos
Hormônio Liberador da Corticotropina/biossíntese , Regulação da Expressão Gênica , Receptores de GABA-A/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Animais , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Agonistas GABAérgicos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Piridinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Receptores de Glutamato Metabotrópico/antagonistas & inibidores
9.
Med Sci Monit ; 16(9): BR307-12, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20802407

RESUMO

BACKGROUND: The present study analyzed the neuroprotective effects of topiramate on 6-hydroxydopamine (6-OHDA)-induced toxicity in primary dopaminergic mesencephalic neuronal cell cultures. MATERIAL/METHODS: Through the use of tyrosine hydroxylase and microtubule-associated protein 2 immunocytochemistry, the morphology and development of dopaminergic neurons was observed. Hoechst33258 and propidium iodide (PI) double staining was used to determine cell membrane penetrability and apoptosis by fluorescent microscopy. Methyl thiazole tetrazolium was used to assay cell viability and metabolism. The cells were assigned to 3 groups: (1) control: primary cultured neurons; (2) 6-OHDA: primary cultured neurons and 6-OHDA; and (3) topiramate (TPM) protection: primary cultured neurons and 6-OHDA, treated with various concentrations (10, 50, and 100 microM) of TPM. RESULTS: Hoechst 33258 and PI double immunofluorescence revealed that the number of dying cells after 6-OHDA treatment was greater than after TPM treatment. Compared with the 6-OHDA group, there were more neurons with greater cell viability in the 6-OHDA plus TPM group. CONCLUSIONS: Topiramate was shown to provide protection to dopaminergic neurons exposed to 6-OHDA by reducing cell apoptosis and enhancing cell viability. The neuroprotective effects of TPM were dose-dependent.


Assuntos
Dopamina/metabolismo , Frutose/análogos & derivados , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Bisbenzimidazol/metabolismo , Contagem de Células , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Imunofluorescência , Formazans/metabolismo , Frutose/farmacologia , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/citologia , Neurônios/enzimologia , Neurônios/metabolismo , Propídio/metabolismo , Ratos , Ratos Sprague-Dawley , Coloração e Rotulagem , Sais de Tetrazólio/metabolismo , Topiramato , Tirosina 3-Mono-Oxigenase/metabolismo
10.
Neuropharmacology ; 59(7-8): 612-8, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20727364

RESUMO

Conflict procedures can be used to study the receptor mechanisms underlying the anxiolytic effects of benzodiazepines and other GABA(A) receptor modulators. In the present study, we first determined the efficacy and binding affinity of the benzodiazepine diazepam and recently synthesized GABA(A) receptor modulators JY-XHe-053, XHe-II-053, HZ-166, SH-053-2'F-S-CH3 and SH-053-2'F-R-CH3 at GABA(A) receptors containing α1, α2, α3 and α5 subunits. Results from these studies suggest that each compound displayed lower efficacy at GABA(A) receptors containing α1 subunits and varying degrees of efficacy and affinity at GABA(A) receptors containing α2, α3 and α5 subunits. Next, we assessed their anxiolytic effects using a rhesus monkey conflict procedure in which behavior was maintained under a fixed-ratio schedule of food delivery in the absence (non-suppressed responding) and presence (suppressed responding) of response-contingent electric shock. Relatively non-selective compounds, such as diazepam and JY-XHe-053 produced characteristic increases in rates of suppressed responding at low to intermediate doses and decreased the average rates of non-suppressed responding at higher doses. XHe-II-053 and HZ-166 also produced increases in suppressed responding at low to intermediate doses, but were ineffective at decreasing rates of non-suppressed responding, consistent with their relatively low efficacy at GABA(A) receptors containing α1 and α5 subunits. In contrast, SH-053-2'F-S-CH3 and SH-053-2'F-R-CH3 produced only partial increases in suppressed responding and were ineffective on non-suppressed responding, consistent with their profiles as partial agonists at GABA(A) receptors containing α2, α3 and α5 subunits. These behavioral effects suggest that the anxiolytic and rate-reducing effects of GABA(A) receptor positive modulators are dependent on their relative efficacy and affinity at different GABA(A) receptor subtypes.


Assuntos
Alquinos/farmacologia , Ansiolíticos/farmacologia , Benzodiazepinas/farmacologia , Diazepam/análogos & derivados , Moduladores GABAérgicos/farmacologia , Imidazóis/farmacologia , Alquinos/química , Animais , Benzodiazepinas/química , Ligação Competitiva , Linhagem Celular , Diazepam/química , Diazepam/farmacologia , Feminino , Humanos , Imidazóis/química , Técnicas In Vitro , Macaca mulatta , Masculino , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Técnicas de Patch-Clamp , Ensaio Radioligante , Ratos , Receptores de GABA-A/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Xenopus laevis
11.
Prog Neuropsychopharmacol Biol Psychiatry ; 34(2): 376-86, 2010 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-20074611

RESUMO

Over the last years, genetic studies have greatly improved our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA(A) receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA(A) receptors containing the alpha(1) subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of, respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA(A) receptors containing the alpha(1) subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably alpha(1) receptor-mediated sedative effects of GABA(A) modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at alpha(2)- and alpha(3)-GABA(A) receptors, may have been partly connected with its preferential affinity at alpha(5)-GABA(A) receptors coupled with weak agonist activity at alpha(1)-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at alpha(1) GABA(A) receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at alpha(1)- and alpha(5)-GABA(A) receptors is sufficient for eliciting sedation.


Assuntos
Ligação Competitiva/fisiologia , Atividade Motora/fisiologia , Subunidades Proteicas/metabolismo , Receptores de GABA-A/química , Receptores de GABA-A/fisiologia , Análise de Variância , Animais , Benzodiazepinas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Ligação Competitiva/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , GABAérgicos/farmacologia , Ligantes , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Atividade Motora/efeitos dos fármacos , Oócitos , Técnicas de Patch-Clamp/métodos , Ligação Proteica/efeitos dos fármacos , Subunidades Proteicas/efeitos dos fármacos , Subunidades Proteicas/genética , Subunidades Proteicas/fisiologia , Ratos , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/genética , Relação Estrutura-Atividade , Transdução Genética/métodos , Xenopus
13.
J Med Chem ; 52(7): 1795-8, 2009 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-19275170

RESUMO

The antiseizure activity of benzodiazepines (BDZs) 1-5 in mice and rats as animal models is described. These BDZs have selective efficacy for alpha2beta3gamma2 and alpha3beta3gamma2 GABA(A)-receptors. Significant anticonvulsant activity with little or no motor impairment and therapeutic indexes (TI) of 2.8-44 (mice, ip) were observed for compounds 2-4 in the subcutaneous metrazole seizure (scMET) test. In rats, orally (po) the TI was >5 to 105. These compounds represent novel leads in the search for anticonvulsants devoid of sedative, ataxic, and amnestic side effects.


Assuntos
Anticonvulsivantes/síntese química , Benzodiazepinas/síntese química , Receptores de GABA-A/metabolismo , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/toxicidade , Benzodiazepinas/farmacologia , Benzodiazepinas/toxicidade , Convulsivantes , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Excitação Neurológica/efeitos dos fármacos , Ligantes , Camundongos , Pentilenotetrazol , Ratos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Relação Estrutura-Atividade
14.
Neuropsychopharmacology ; 33(2): 332-9, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17392731

RESUMO

Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA(A) receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABA(A) receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of alpha(1) subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by alpha(5)-containing GABA(A) receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.


Assuntos
Benzodiazepinas/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Receptores de GABA-A/fisiologia , Análise de Variância , Animais , Masculino , Subunidades Proteicas/efeitos dos fármacos , Subunidades Proteicas/fisiologia , Ratos , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos
15.
Inorg Chem ; 46(24): 10044-6, 2007 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-17958359

RESUMO

An alpha-quartz-mimetic chiral coordination network of [Ag(L1)(CF3SO3)]n (L1=5,5'-bipyrimidine), after treatment with PF6- anions, undergoes a solution-state structural transformation toward [Ag(L1)(PF6)]n with a cristobalite-mimetic chiral structures. This structural transformation is accompanied by substantial enhancement in the fluorescent intensity and in the second-harmonic-generation response. The results also demonstrate an effective design strategy based on the spontaneous resolution route for the preparation of chiral architectures.


Assuntos
Compostos Organometálicos/síntese química , Quartzo/química , Dióxido de Silício/química , Prata/química , Estrutura Molecular , Compostos Organometálicos/química
16.
Org Lett ; 9(8): 1469-71, 2007 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-17358071

RESUMO

[reaction: see text] A palladium-catalyzed domino sequence was developed to rapidly construct the core structure of neosarpagine and other quinuclidine-related alkaloids. The cyclization of ketone 11 to ethylidene 4 with Pd(dba)2, DPEphos, LiHMDS, and ZnCl2 in THF represents a new domino process wherein a nonstabilized enolate served as a nucleophile.


Assuntos
Alcaloides Indólicos/química , Catálise , Alcaloides Indólicos/síntese química , Cetonas/química , Modelos Moleculares , Estrutura Molecular , Oxindois , Paládio/química , Quinuclidinas/química
17.
J Nat Prod ; 70(1): 75-82, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17253853

RESUMO

The stable conformations of both the trans- and cis-1,3-disubstituted Nb-benzyl stereoisomers of the Pictet - Spengler reaction have been determined by NMR spectroscopy and X-ray crystallography in order to better understand the C(1) -N(2) cis- to trans-isomerization process. In the Na-H series, the chair conformation was preferred for the trans-isomer 3a, while the cis-isomer 3b existed predominantly in the boat form. However, in the Na-methyl series (1a, 1b, 2a, 2b), both the cis (1b, 2b) and trans (1a, 2a) diastereomers existed in the chair conformation to relieve the A(1,2)-strain between the Na-methyl function and the substituent at C(1). The difference in the preferred conformations of the cis-isomers in the Na-H and Na-methyl series (as compared to the preferred conformations in the trans-isomers) can be employed to understand the reduced rate of epimerization of cis-2b into trans-2a as compared to 3b into 3a. This provides the structural basis for the carbocation-mediated intermediate in the C(1) - N(2) scission process.


Assuntos
Compostos de Benzil/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Estereoisomerismo
18.
Psychopharmacology (Berl) ; 187(3): 321-30, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16783540

RESUMO

RATIONALE: Benzodiazepine agonists characteristically increase food intake in humans and non-human subjects, and the underlying mechanisms of this effect are not understood completely. OBJECTIVE: Compounds with selectivity for GABAA receptor subtypes were used to evaluate the role of GABAA receptors containing alpha1 and alpha5 subunits (alpha1GABAA and alpha5GABAA receptors, respectively) in benzodiazepine-induced increases in sucrose pellet consumption. MATERIALS AND METHODS: Adult male squirrel monkeys (N=4-6), maintained under free-feeding conditions, were administered with intramuscular injections of the nonselective benzodiazepines diazepam and alprazolam, the alpha1GABAA-preferring compounds zolpidem and zaleplon, or the alpha5GABAA-preferring agonist QH-ii-066 before daily 10-min periods when sucrose pellets were available. In a separate experiment, observable behavioral effects (e.g., ataxia and procumbent posture) were quantified after administration of alprazolam, zaleplon, and QH-ii-066. To further assess the roles of GABAA receptor subtypes, zolpidem-induced increases in pellet consumption were re-evaluated after pretreatment with nonselective antagonist flumazenil, the alpha1GABAA-preferring antagonist beta-carboline-3-carboxylate-t-butyl ester (BCCT), or QH-ii-066. RESULTS: Alprazolam, diazepam, zolpidem, and zaleplon but not QH-ii-066 significantly increased sucrose pellet consumption. In addition, all agonists decreased locomotion and environment-directed behavior as well as engendered ataxia and procumbent posture. For all compounds except QH-ii-066, these behaviors occurred at doses similar to those that increased pellet consumption. Flumazenil and BCCT, but not QH-ii-066, antagonized zolpidem-induced increases in pellet consumption in a surmountable fashion. CONCLUSION: These results suggest that the alpha1GABAA receptor subtype plays a key role in benzodiazepine-induced increases in consumption of palatable food, whereas the alpha5GABAA receptor subtype may not be involved in this effect.


Assuntos
Benzodiazepinas/farmacologia , Receptores de GABA-A/fisiologia , Sacarose/administração & dosagem , Alprazolam/farmacologia , Animais , Diazepam/farmacologia , Flumazenil/farmacologia , Masculino , Piridinas/farmacologia , Receptores de GABA-A/classificação , Saimiri , Zolpidem
19.
Inorg Chem ; 45(6): 2430-7, 2006 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-16529462

RESUMO

A 0D discrete molecule [Co(3,5-pdc)(H2O)5].2H2O (1) was obtained in quantitative yield from the reaction of CoCl2.6H2O and pyridine-3,5-dicarboxylate (3,5-pdc) in pure water solvent at ambient temperature. While a 1D zigzag chain species, [{Co(3,5-pdc)(H2O)4}.H2O]n (2), was produced in a water-rich environment, a 2D layer compound, [Co(3,5-pdc)(H2O)2]n (3), with a 6(3) topology was generated under a water-reduced condition and a 2D sheet structure, [{Cu(3,5-pdc)(py)2}.H2O.EtOH]n (4), was formed under a water-poor condition. Compounds 1, 2, and 4 were characterized by single-crystal X-ray diffraction analysis. The 1D zigzag chain 2 shows a recoverable collapsing property. Compound 4 adopts a 2D sheet structure with a 4.8(2) topology, observed for the first time for the 3,5-pdc-related metal-organic frameworks. Water content was found to be an important factor in determining the topologies of the products in the self-assembly of divalent metal ions (Co2+, Cu2+) and pyridine-3,5-dicarboxylate under mild conditions.

20.
Inorg Chem ; 45(1): 295-303, 2006 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-16390068

RESUMO

A self-assembly of AgClO(4) with a Schiff-base ligand N,N'-bis(pyridin-2-ylmethylene)benzene-1,4-diamine (1) gave a 1D zigzag polymeric array [[Ag(2)(C(18)H(14)N(4))(2)](ClO(4))(2)(CH(3)CN)](n) (3), while the self-assembly of AgClO(4) with 3,3'-dimethyl-N,N'-bis(pyridin-2-ylmethylene)biphenyl-4,4'-diamine (2) afforded the molecular rectangle [[Ag(2)(C(26)H(22)N(4))(2)](ClO(4))(2)] (4). The structures of 3 and 4 were characterized by single-crystal X-ray diffraction analysis. Structural data for 3 indicate that the Ag(I) ion is coordinated by two ligands of 1 in a distorted tetrahedral fashion thereby leading to a 1D zigzag polymeric array. The zigzag chains are interdigitated with weak pi-pi stacking interactions. The structure of 4 consists of a discrete molecular rectangle where the silver atom has a distorted square-planar coordination with the pyridyl ligands and azomethine nitrogen atoms of 2. An intramolecular pi-pi interaction between the phenyl rings of adjacent Schiff-base 2 functions to stabilize the rectangular architecture. The Ag(I)-Schiff-base coordination polymer 3 is not stable in solution. The degradation and reorganization of 3 to form a [2 x 2] grid architecture [[Ag(4)(C(26)H(22)N(4))(4)](ClO(4))(4)] (3g) was supported in a FAB-MS study. The rectangular structure of 4 remains intact in solution at ambient temperature. The complexes 3g and 4 exhibit unusual luminescence behavior in solution at room temperature with significantly red-shifted emission in the visible region.

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