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1.
Neuroimage ; 181: 347-358, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29886144

RESUMO

The discovery of hemodynamic (BOLD-fMRI) resting-state networks (RSNs) has brought about a fundamental shift in our thinking about the role of intrinsic brain activity. The electrophysiological underpinnings of RSNs remain largely elusive and it has been shown only recently that electric cortical rhythms are organized into the same RSNs as hemodynamic signals. Most electrophysiological studies into RSNs use magnetoencephalography (MEG) or scalp electroencephalography (EEG), which limits the spatial resolution with which electrophysiological RSNs can be observed. Due to their close proximity to the cortical surface, electrocorticographic (ECoG) recordings can potentially provide a more detailed picture of the functional organization of resting-state cortical rhythms, albeit at the expense of spatial coverage. In this study we propose using source-space spatial independent component analysis (spatial ICA) for identifying generators of resting-state cortical rhythms as recorded with ECoG and for reconstructing their functional connectivity. Network structure is assessed by two kinds of connectivity measures: instantaneous correlations between band-limited amplitude envelopes and oscillatory phase-locking. By simulating rhythmic cortical generators, we find that the reconstruction of oscillatory phase-locking is more challenging than that of amplitude correlations, particularly for low signal-to-noise levels. Specifically, phase-lags can both be over- and underestimated, which troubles the interpretation of lag-based connectivity measures. We illustrate the methodology on somatosensory beta rhythms recorded from a macaque monkey using ECoG. The methodology decomposes the resting-state sensorimotor network into three cortical generators, distributed across primary somatosensory and primary and higher-order motor areas. The generators display significant and reproducible amplitude correlations and phase-locking values with non-zero lags. Our findings illustrate the level of spatial detail attainable with source-projected ECoG and motivates wider use of the methodology for studying resting-state as well as event-related cortical dynamics in macaque and human.


Assuntos
Ritmo beta/fisiologia , Conectoma/métodos , Eletrocorticografia/métodos , Processamento de Imagem Assistida por Computador/métodos , Córtex Motor/fisiologia , Rede Nervosa/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Macaca , Imageamento por Ressonância Magnética , Córtex Motor/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Córtex Somatossensorial/diagnóstico por imagem
2.
Hautarzt ; 65(12): 1062-5, 2014 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-25260302

RESUMO

A 67-year-old man presented with a maculopapular exanthem which started over the major joints. Within a few days, it spread to the entire skin surface and was accompanied by blisters as well as changes of the oral mucosa. The histological examination revealed subepidermal blistering. Targeted laboratory examinations detected serum antibodies against the epidermal basement membrane and autoantibodies against type VII collagen. The findings supported the diagnosis of a generalized inflammatory epidermolysis bullosa acquisita with mucosal involvement.


Assuntos
Vesícula/diagnóstico , Vesícula/etiologia , Epidermólise Bolhosa Adquirida/complicações , Epidermólise Bolhosa Adquirida/diagnóstico , Idoso , Diagnóstico Diferencial , Exantema , Reações Falso-Positivas , Humanos , Masculino , Doenças Raras/diagnóstico , Dermatopatias Virais/complicações , Dermatopatias Virais/diagnóstico
3.
Hautarzt ; 63(9): 693-703, 2012 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-22956032

RESUMO

Recurrent aphthous ulcers are the most common inflammatory lesions of the oral mucosa, occurring in up to 10% of the population and even more common in children. The history, morphological characteristics, predilection sides and typical stages of aphthae help to distinguish them from other diseases that may exhibit aphthous-like lesions. Underlying diseases should be excluded. The main goals of therapy are to minimize pain and functional disabilities as well as decrease frequency and severity of recurrences. Topical symptomatic relief is the standard of care for simple cases of recurrent aphthosis. In cases of major aphthosis or systemic involvement, topical therapies are still useful but should be combined with systemic therapy, such as colchicine, pentoxifylline or prednisolone. In case of Adamantiades-Behçet disease, systemic immunomodulatory drugs can inhibit the development of new lesions. This overview summarizes morphological and presentation forms of aphthae, differential diagnoses and evidence-based therapeutic possibilities.


Assuntos
Medicina Baseada em Evidências , Fatores Imunológicos/administração & dosagem , Imunossupressores/administração & dosagem , Estomatite Aftosa/tratamento farmacológico , Estomatite Aftosa/prevenção & controle , Humanos , Prevenção Secundária , Estomatite Aftosa/diagnóstico
4.
Neuroradiol J ; 25(6): 725-38, 2012 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-24029186

RESUMO

Some rare neurological diseases affecting children have no well defined etiology and pathogenetic mechanisms. In this article diseases like Reye syndrome, Behçet disease, pediatric neurosarcoidosis, Posterior Reversible Encephalopathy Syndrome are described. Some of the main neuroradiological differential aspects are also critically considered. Reye syndrome is characterized by symmetric thalamic, white matter and basal ganglia lesions, in children with recent history of salycilates or immunosuppressive drugs intake. The most typical MRI feature of neurosarcoidosis is basilar meningeal thickening and enhancement with intraparenchymal enhancing nodules and white matter focal abnormalities. The classical distribution of lesions helps differential diagnosis with infectious meningoencephalitis. Differential diagnosis with relapsing-remitting multiple sclerosis his helped by the evidence of meningeal abnormalities. Neuro-Behçet is characterized by mesodiencephalic lesions in children with encephalopathy and coexistence of oral and genital ulcers and ocular abnormalities. PRES can be differentiated from vasculitis for the typical posterior white matter involvement and the different clinical features.

5.
Neuroimage ; 49(2): 1469-78, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19778620

RESUMO

Fetal magnetoencephalography (fMEG) is used to study neurological functions of the developing fetus by measuring magnetic signals generated by electrical sources within the fetal brain. For this aim either auditory or visual stimuli are presented and evoked brain activity or spontaneous activity is measured at the sensor level. However a limiting factor of this approach is the low signal to noise ratio (SNR) of recorded signals. To overcome this limitation, advanced signal processing techniques such as spatial filters (e.g., beamformer) can be used to increase SNR. One crucial aspect of this technique is the forward model and, in general, a simple spherical head model is used. This head model is an integral part of a model search approach to analyze the data due to the lack of exact knowledge about the location of the fetal head. In the present report we overcome this limitation by a coregistration of volumetric ultrasound images with fMEG data. In a first step we validated the ultrasound to fMEG coregistration with a phantom and were able to show that the coregistration error is below 2 cm. In the second step we compared the results gained by the model search approach to the exact location of the fetal head determined on pregnant mothers by ultrasound. The results of this study clearly show that the results of the model search approach are in accordance with the location of the fetal head.


Assuntos
Encéfalo/embriologia , Encéfalo/fisiologia , Ecoencefalografia/métodos , Magnetoencefalografia/métodos , Diagnóstico Pré-Natal/métodos , Ultrassonografia Pré-Natal/métodos , Estimulação Acústica , Algoritmos , Percepção Auditiva/fisiologia , Ecoencefalografia/instrumentação , Potenciais Evocados , Feminino , Cabeça , Humanos , Processamento de Imagem Assistida por Computador , Magnetoencefalografia/instrumentação , Modelos Teóricos , Imagens de Fantasmas , Estimulação Luminosa , Gravidez , Diagnóstico Pré-Natal/instrumentação , Ultrassonografia Pré-Natal/instrumentação , Percepção Visual/fisiologia
6.
Urologia ; 76 Suppl 15: 10-4, 2009.
Artigo em Italiano | MEDLINE | ID: mdl-21104677
7.
Urol Int ; 79 Suppl 1: 37-46, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17726351

RESUMO

In recent years stone disease has become more widespread in developed countries. At present the prevalence is 5.2 and 15% of men and 6% of women are affected. The increase is linked to changes in lifestyle, eating patterns and obesity which has become very common. The 'metabolic syndrome' includes all the diseases, e.g. hypertension, lipid imbalances, type 2 diabetes mellitus, gout and cardiovascular disease, which are concomitant in the majority of stone formers. Dietary patterns, besides leading to stone formation, also determine stone chemistry. With a diet that is rich in oxalates, calcium oxalate will constitute 75% of stones, struvite 10-20%, uric acid 5-6% and cystine 1%. As approximately 50% of patients with stones suffer recurrences, metabolic and/or pharmacological prophylaxis is recommended.


Assuntos
Suplementos Nutricionais , Estilo de Vida , Fármacos Renais/uso terapêutico , Cálculos Urinários/prevenção & controle , Urolitíase/prevenção & controle , Alopurinol/uso terapêutico , Oxalato de Cálcio/metabolismo , Cistina/metabolismo , Dieta , Ingestão de Líquidos , Humanos , Prevenção Secundária , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Ácido Úrico/metabolismo , Cálculos Urinários/metabolismo , Cálculos Urinários/terapia , Urolitíase/metabolismo , Urolitíase/terapia
9.
Farmaco ; 57(11): 889-95, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12484537

RESUMO

The synthesis and pharmacology of two potential glutamic acid receptor ligands are described. Preparation of the bicyclic 3-hydroxy-delta2-isoxazoline-cyclopentane derivatives (+/-)-7 and (+/-)-8 was accomplished via 1,3-dipolar cycloaddition of bromonitrile oxide to suitably protected 1-amino-cyclopent-3-enecarboxylic acids. Their structure was established using a combination of 1H NMR spectroscopy and molecular mechanics calculations carried out on the intermediate cycloadducts (+/-)-11 and (+/-)-12. Amino acid derivatives (+/-)-7 and (+/-)-8 were assayed at ionotropic and metabotropic glutamic acid receptor subtypes and their activity compared with that of trans-ACPD and cis-ACPD. The results show that the replacement of the omega-carboxylic group of the model compounds with the 3-hydroxy-delta2-isoxazoline moiety abolishes or reduces drastically the activity at the metabotropic glutamate receptors. Conversely, on passing from cis-ACPD to derivative (+/-)-8, the agonist activity at NMDA receptors is almost unaffected.


Assuntos
Cicloleucina/análogos & derivados , Glutamatos/síntese química , Glutamatos/farmacologia , Receptores de Glutamato/efeitos dos fármacos , Aminoácidos/química , Animais , Ligação Competitiva/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Ciclização , Cicloleucina/síntese química , Cicloleucina/farmacologia , Eletrofisiologia , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Técnicas In Vitro , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Ratos , Receptores de AMPA/efeitos dos fármacos , Receptores de Ácido Caínico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Estereoisomerismo , Ácido gama-Aminobutírico/fisiologia
10.
Bioorg Med Chem Lett ; 11(4): 463-6, 2001 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-11229748

RESUMO

The synthesis and anticonvulsant activity of 1-aryl-7,8-methylenedioxy-1,2,3,5-tetrahydro-4H-2,3-benzodiazepin-4-(thi)ones (4a-d) and their 3-N-alkylcarbamoyl derivatives (4e-h) are reported. The new compounds possess marked anticonvulsant properties, comparable to those of the dehydro analogues 3 and higher than that of GYKI 52466 (1). Noteworthy, compound 4c shows a longer-lasting anticonvulsant activity. Electrophysiological experiments show that derivative 4c is less effective than 1 and 3c to reduce the KA-evoked currents in cerebellar granule neurons.


Assuntos
Anticonvulsivantes/síntese química , Benzodiazepinas , Receptores de AMPA/antagonistas & inibidores , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Camundongos , Camundongos Endogâmicos DBA
11.
Mini Rev Med Chem ; 1(3): 243-53, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12369971

RESUMO

There is increasing evidence of the potential therapeutic utility of glutamate receptor antagonists in the treatment of several neurodegenerative disorders, including stroke and epilepsy. In the last few years noncompetitive AMPA receptor antagonists have received considerable attention due to their therapeutic potentiality. The discovery of GYKI 52466, the prototype of noncompetitive AMPA receptor antagonists endowed with anticonvulsant and neuroprotective properties, induced growing interest on 2,3-benzodiazepine derivatives. This review covers the chemistry and pharmacology of this important class of AMPA receptor antagonists.


Assuntos
Ansiolíticos/síntese química , Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de AMPA/antagonistas & inibidores , Ansiolíticos/química , Ansiolíticos/uso terapêutico , Benzodiazepinas/química , Desenho de Fármacos , Antagonistas de Aminoácidos Excitatórios/química , Humanos , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Relação Estrutura-Atividade
12.
J Affect Disord ; 67(1-3): 105-14, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11869757

RESUMO

BACKGROUND: Although mixed states were classically described as various concomitant admixtures of depression and mania, the official current definitions in both DSM-IV and ICD-10 tend to restrict the concept to manic patients with full syndromal depression. Recent research has actually shown that mania with few depressive symptoms constitutes the most prevalent clinical presentation of mixed or dysphoric mania. Major depressive patients with few concomitant manic symptoms are not officially recognized within the current nosology. In this paper we attempt to delineate the clinical profile of such depressive mixed states in the context of bipolar I disorder. METHODS: In the Pisa day center, we studied 195 bipolar I patients who either met Pisa criteria for bipolar mixed state (n=159) or DSM-III-R criteria for major depressive episode (bipolar major depression or B-MD, n=36). Of the 159 patients identified by Pisa criteria as mixed state, 86 also met the criteria of the DSM-III-R for mixed episode (core mixed state or MS group), while 32 met the DSM III-R criteria for major depressive episode (provisionally defined as depressive mixed states, D-MS); the remaining patients (n=41, 25.7%) with predominatly manic picture were not included in the present comparisons. RESULTS: The three groups (B-MD, MS and D-MS) had close similarities in clinical and sociodemographic characteristics such as age, sex distribution, marital status, schooling, residence, age at onset, age of first treatment, age of first hospitalization, degree of chronicity of the index episode, stressor within the 6 months before the index episode, lifetime suicide attempts and premorbid temperament. First degree family history for bipolar illness and that for other mental disorders was also similar, except for major depression that was more common among the relatives of D-MS. MS and D-MS were further distinguished from B-MD by the fact that the latter followed a more 'cyclic' course with shorter yet greater number of episodes, and which began with a pure depressive episode; by contrast, MS and D-MS had fewer episodes of longer duration, less interepisodic remission, and tended to begin with a mixed episode. Incongruous psychotic features were more common in the two mixed groups compared to B-MD, and the most common features of the D-MS group were agitation, psychotic depression with irritable mood, pressured speech and/or flight of ideas. LIMITATION: It was not feasible to collect information blind to clinical status in patients with severe psychotic mood states. CONCLUSION: These data confirm the existence of psychotic agitated depressive mixed states with flight of ideas, distinct from cyclic retarded pure bipolar depressive states. The recognition of these affective states is clinically important to protect patients from the potentially harmful indiscriminate use of antidepressants and to provide them with the benefits of an anticonvulsant, a short-term neuroleptic, or ECT.


Assuntos
Transtorno Bipolar/psicologia , Depressão/psicologia , Adulto , Afeto , Transtorno Bipolar/classificação , Depressão/classificação , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Agitação Psicomotora , Recidiva , Índice de Gravidade de Doença
13.
Life Sci ; 67(3): 317-26, 2000 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-10983875

RESUMO

The enantiomers desoxymuscarine 6 were tested in vitro on guinea pig tissues, and their muscarinic potency was evaluated at M2 (heart force and rate) and M3 (ileum and bladder) receptor subtypes together with the enantiomers of the parent compound muscarine 1. The eutomers (+)-1 and (+)-6 and distomers (-)-1 and (-)-6 were also assayed in vivo on pithed rat. Affinity, relative efficacy and enantio-selectivity were also determined for the compounds under study at M2 (heart force and rate) and M3 (ileum and bladder), in order to investigate muscarinic receptor heterogeneity. The results of this study have been discussed in comparison with the data previously reported for the structurally related fluoromuscarine (+)-4 and difluoromuscarines (+)-5 and (-)-5.


Assuntos
Muscarina/análogos & derivados , Agonistas Muscarínicos/farmacologia , Animais , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Íleo/efeitos dos fármacos , Técnicas In Vitro , Masculino , Muscarina/farmacologia , Agonistas Muscarínicos/isolamento & purificação , Contração Muscular/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Ratos , Receptor Muscarínico M2 , Receptor Muscarínico M3 , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/fisiologia , Estereoisomerismo , Relação Estrutura-Atividade , Bexiga Urinária/efeitos dos fármacos
14.
J Med Chem ; 43(15): 2851-9, 2000 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-10956193

RESUMO

In this paper, we describe the synthesis of a series of novel substituted 4-aryl-6,7-methylenedioxyphthalazin-1(2H)-ones. The anticonvulsant activity of these compounds against audiogenic seizures was evaluated in DBA/2 mice after intraperitoneal (ip) injection. Most of these derivatives are more active than 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA receptor antagonist. As deduced by the rotarod test, all the compounds exhibit a toxicity lower than that of 1. Within the series of derivatives submitted to investigation, 4-(4-aminophenyl)-2-butylcarbamoyl-6,7-methylenedioxyphthalazin -1(2H)-one (21) proved to be the most active compound and is 11-fold more potent than 1 (i.e., ED50 3.25 micromol/kg for 21 versus ED50 35.8 micromol/kg for 1). When compared to 1, compound 21 as well as its analogue 4-(4-aminophenyl)-6,7-methylenedioxyphthalazin-1(2H)-one (16) show a longer lasting anticonvulsant activity. Compound 21 also effectively suppresses seizures induced in Swiss mice by maximal electroshock (MES) and pentylenetetrazole (PTZ). Furthermore, it antagonizes in vivo seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), 2-amino-3-(3-hydroxy-5-tert-butyl-isoxazol-4-yl)propionic acid (ATPA), and kainate (KA), and its anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 16 and 21 to antagonize KA-evoked currents in primary cultures of granule neurons was tested. They behaved as antagonists, but they proved to be less effective than 1 and 1-(4-aminophenyl)-3,4-dihydro-4-methyl-3-N-methylcarbamoyl-7,8-met hylenedioxy-5H-2,3-benzodiazepine (2, GYKI 53655) to reduce the KA-evoked currents.


Assuntos
Anticonvulsivantes/síntese química , Ftalazinas/síntese química , Estimulação Acústica , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Células Cultivadas , Convulsivantes , Avaliação Pré-Clínica de Medicamentos , Eletrochoque , Agonistas de Aminoácidos Excitatórios , Isoxazóis , Ácido Caínico , Camundongos , Camundongos Endogâmicos DBA , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Pentilenotetrazol , Ftalazinas/química , Ftalazinas/farmacologia , Propionatos , Receptores de AMPA/agonistas , Receptores de Ácido Caínico/agonistas , Convulsões/tratamento farmacológico , Convulsões/etiologia , Relação Estrutura-Atividade , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico
15.
Farmaco ; 55(3): 162-4, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10919071

RESUMO

Regioisomeric 3-carboxyisoxazolinyl prolines (CIP-A and CIP-B) and 3-hydroxyisoxazolinyl prolines [(+/-)-8 and (+/-)-9] were synthesized and assayed for glutamate receptor activity. CIP-A [(+/-)-6] showed a convulsant activity evaluated in vivo on DBA/2 mice, higher than AMPA and similar to kainic acid. The eutomer of CIP-A [CIP-AS, (-)-6], obtained from (S)-3,4-didehydroproline, evidenced common stereochemical requirements with AMPA and kainic acid.


Assuntos
Glutamatos/síntese química , Animais , Desenho de Fármacos , Agonistas de Aminoácidos Excitatórios/síntese química , Agonistas de Aminoácidos Excitatórios/farmacologia , Glutamatos/farmacologia , Camundongos , Conformação Molecular , Receptores de AMPA/agonistas , Receptores de Ácido Caínico/agonistas , Receptores de N-Metil-D-Aspartato/agonistas , Relação Estrutura-Atividade
16.
Compr Psychiatry ; 41(1): 13-8, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10646613

RESUMO

In 320 patients with established bipolar I disorder, we examined the past course on the basis of polarity at onset (depressive, mixed, and manic). Despite the obvious limitations of retrospective methodology, information on course parameters in a large sample of affective disorders is most practically obtained by such methodology. We believe that our systematic interview of patients and their relatives--as well as the systematic study of their records--minimized potential biases. Depressive onsets were the most common, accounting for 50%, followed by mixed and manic onsets in about equal proportion. In general, the polarity of episodes over time reflected polarity at onset. Those with depressive onset had significantly higher levels of rapid cycling, as well as suicide attempts, but were significantly less likely to develop psychotic symptoms. Mixed onsets, too, had high rates of suicide attempts, but differed from depressive onsets in having significantly more chronicity yet negligible rates of rapid cycling at follow-up evaluation. Because cases with depressive onset had received significantly higher rates of psychopharmacologic treatment, our data are compatible with the hypothesis that antidepressants may play a role in the induction of rapid cycling. Overall, our data support the existence of distinct longitudinal patterns within bipolar I disorder, which in turn appear correlated with the polarity at onset. In particular, rapid cycling and mixed states emerge as distinct psychopathologic processes.


Assuntos
Antidepressivos/efeitos adversos , Transtorno Bipolar/psicologia , Transtorno Ciclotímico/induzido quimicamente , Transtorno Depressivo/psicologia , Adolescente , Adulto , Idade de Início , Idoso , Transtorno Bipolar/tratamento farmacológico , Transtorno Ciclotímico/tratamento farmacológico , Transtorno Ciclotímico/psicologia , Transtorno Depressivo/tratamento farmacológico , Feminino , Humanos , Entrevista Psicológica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Socioeconômicos , Estatísticas não Paramétricas , Tentativa de Suicídio/estatística & dados numéricos
17.
Farmaco ; 55(8): 535-43, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11132731

RESUMO

Novel derivatives of natural muscarine and allo-muscarine, i.e. the benzyl ethers (-)-10 and (-)-12 and the benzoate (-)-13, were synthesized in very high enantiomeric excess. Target compounds were tested in vitro on guinea pig tissues, and their muscarinic potency was evaluated at M2 (heart force and rate) and M3 (ileum and bladder) receptor subtypes. The derivatives under study were also assayed in vivo on pithed rat. In addition, muscarinic receptor heterogeneity was investigated by determining the affinity and the relative efficacy of compounds (-)-10, (-)-12 and (-)-13 at M2 (heart force and rate) and M3 (ileum and bladder) receptor subtypes.


Assuntos
Muscarina/análogos & derivados , Receptores Muscarínicos/efeitos dos fármacos , Animais , Cobaias , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Muscarina/síntese química , Muscarina/farmacologia , Contração Muscular/efeitos dos fármacos , Ratos , Estereoisomerismo
18.
Life Sci ; 67(6): 717-23, 2000 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-12659177

RESUMO

Two subsets of tertiary amines (1a-6a) and methiodides (1b-6b) with a structural resemblance to oxotremorine and oxotremorine-M were tested at rabbit vas deferens (M1), guinea pig left atrium (M2), guinea pig ileum and urinary bladder (M3) muscarinic receptor subtypes. The pharmacological profile of the derivatives under study has been discussed by evaluating their potency, affinity and efficacy as well as the regional differences in muscarinic receptor occupancy.


Assuntos
Agonistas Muscarínicos/farmacologia , Oxotremorina/análogos & derivados , Oxotremorina/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Estimulação Elétrica , Cobaias , Átrios do Coração/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Íleo/efeitos dos fármacos , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Contração Miocárdica/efeitos dos fármacos , Coelhos , Receptor Muscarínico M1 , Receptor Muscarínico M2 , Receptor Muscarínico M3 , Bexiga Urinária/efeitos dos fármacos , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/metabolismo
19.
J Med Chem ; 42(21): 4414-21, 1999 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-10543885

RESUMO

We have previously shown that 1-aryl-3,5-dihydro-7, 8-methylenedioxy-4H-2,3-benzodiazepin-4-ones (3) possess marked anticonvulsant properties and antagonize seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) in analogy to the structurally related 1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA/kainate receptor antagonist. We now report the synthesis of 3-(N-alkylcarbamoyl)-1-aryl-3,5-dihydro-7, 8-methylenedioxy-4H-2,3-benzodiazepin-4-ones (4a-h) and 1-aryl-3, 5-dihydro-7,8-methylenedioxy-4H-2,3-benzodiazepine-4-thiones (5a-c). The activity of all compounds, intraperitoneally (ip) injected, was evaluated against audiogenic seizures in DBA/2 mice and against seizures induced by maximal electroshock (MES) and pentylenetetrazole (PTZ) in Swiss mice. Some of the new compounds 4 and 5 showed remarkable anticonvulsant activity, and their toxicity, as evidenced by the rotarod test, is lower than that of 1. The time course of anticonvulsant activity of derivatives 4b and 5b,c was studied and compared to that of 1 and 3b,c. Compounds 4a,b and 5a-c antagonize seizures induced by AMPA and kainate (KA) and their anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 3c, 4b, and 5c to antagonize KA-evoked currents in primary cultures of granule neurons was tested and compared with that of the parent compounds 1 and 1-(4-aminophenyl)-3, 4-dihydro-4-methyl-3-methylcarbamoyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine (2, GYKI 53655).


Assuntos
Anticonvulsivantes/síntese química , Antagonistas de Aminoácidos Excitatórios/síntese química , Receptores de AMPA/antagonistas & inibidores , Receptores de Ácido Caínico/antagonistas & inibidores , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Células Cultivadas , Convulsivantes , Avaliação Pré-Clínica de Medicamentos , Eletrochoque , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Caínico , Masculino , Camundongos , Camundongos Endogâmicos DBA , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Pentilenotetrazol , Pirrolidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Convulsões/etiologia , Convulsões/fisiopatologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico
20.
J Med Chem ; 42(20): 4099-107, 1999 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-10514280

RESUMO

Regioisomeric 3-carboxyisoxazolinyl prolines [CIP-A (+/-)-6 and CIP-B (+/-)-7] and 3-hydroxyisoxazolinyl prolines [(+/-)-8 and (+/-)-9] were synthesized and assayed for glutamate receptor activity. The tests were carried out in vitro by means of receptor binding techniques, second messenger assays, and the rat cortical wedge preparation. CIP-A showed a good affinity for both 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and kainic acid (KAIN) receptors. These results were confirmed in the cortical slice model where CIP-A displayed an EC(50) value very close to that of AMPA. The convulsant properties of all the compounds were evaluated in vivo on DBA/2 mice after icv injection. CIP-A showed a convulsant activity, measured as tonus and clonus seizures, 18-65 times higher than that produced by AMPA. It was also quite active after ip administration, since it induced seizures in mice at doses as low as 3.2 nmol/mouse. On the basis of the above-reported results we prepared and tested the enantiomers of CIP-A and CIP-B, obtained by reacting (S)-3,4-didehydroproline and (R)-3,4-didehydroproline, respectively, with ethoxycarbonylformonitrile oxide. In all the tests the S-form, CIP-AS [(-)-6], emerged as the eutomer evidencing common stereochemical requirements with the reference compounds AMPA and KAIN. Through modeling studies, carried out on CIP-A, AMPA, and KAIN, active conformations for CIP-AS and AMPA at AMPA receptors as well as for CIP-AS and KAIN at KAIN receptors are suggested.


Assuntos
Agonistas de Aminoácidos Excitatórios/síntese química , Isoxazóis/síntese química , Prolina/análogos & derivados , Pirróis/síntese química , Receptores de AMPA/agonistas , Receptores de Ácido Caínico/agonistas , Animais , Córtex Cerebral/metabolismo , Convulsivantes/síntese química , Convulsivantes/química , Convulsivantes/metabolismo , Convulsivantes/farmacologia , Agonistas de Aminoácidos Excitatórios/química , Agonistas de Aminoácidos Excitatórios/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Técnicas In Vitro , Isoxazóis/química , Isoxazóis/metabolismo , Isoxazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Modelos Moleculares , Conformação Molecular , Prolina/síntese química , Prolina/química , Prolina/metabolismo , Prolina/farmacologia , Pirróis/química , Pirróis/metabolismo , Pirróis/farmacologia , Ensaio Radioligante , Ratos , Estereoisomerismo
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