RESUMO
3-(2(S)-Azetidinylmethoxy)pyridine (A-85380) has been identified recently as a ligand with high affinity for nicotinic acetylcholine receptors (nAChRs). Here we report the synthesis and in vitro nAChR binding of a series of 10 pyridine-modified analogues of A-85380. The novel compounds feature a halogen substituent at position 2, 5, or 6 of the 3-pyridyl fragment. Those with the substituents at position 5 or 6, as well as the 2-fluoro analogue, possess subnanomolar affinity for nAChRs in membranes from rat brain. For these ligands, Ki values range from 11 to 210 pM, as measured by competition with (+/-)-[3H]epibatidine. In contrast, 2-chloro, 2-bromo, and 2-iodo analogues exhibit substantially lower affinity. AM1 quantum chemical calculations demonstrate that the bulky substituents at position 2 cause notable changes in the molecular geometry. The high-affinity members of the series and (+)-epibatidine display a tight fit superposition of low-energy stable conformers. The new ligands with high affinity for nAChRs may be of interest as pharmacological probes, potential medications, and candidates for developing radiohalogenated tracers to study nAChRs.
Assuntos
Azetidinas , Piridinas , Receptores Nicotínicos/metabolismo , Animais , Azetidinas/síntese química , Azetidinas/química , Azetidinas/metabolismo , Ligação Competitiva , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Ligantes , Masculino , Modelos Moleculares , Agonistas Nicotínicos/metabolismo , Prosencéfalo/metabolismo , Piridinas/síntese química , Piridinas/química , Piridinas/metabolismo , Ratos , Ratos Endogâmicos F344 , Relação Estrutura-AtividadeRESUMO
To examine the relationship between PKBS, a 17-kD protein covalently photolabeled by [3H]PK 14105, and its association with peripheral-type benzodiazepine binding sites, rat adrenal mitochondrial fractions were photolabeled with [3H]PK 14105, solubilized in digitonin, and subjected to anion-exchange chromatography over Q-Sepharose. The chromatographic behavior of PKBS was evident as principally two major fractions, signified as Q-I and Q-II. Specific binding sites for [3H]Ro5-4864 and [3H]PK 11195 were also assayed and found to cofractionate with each other and in a manner which coincided with the photolabeled PKBS profile. The Q-I and Q-II fractions were further distinguished based on their different molecular sizes observed by gel filtration, yet both fractions were characterized as containing peripheral-type benzodiazepine recognition sites according to the following criteria. Scatchard analysis of both subpopulations revealed a single class of binding sites for [3H]Ro5-4864 with an apparent KD of 14 nM for Q-I and 22 nM for Q-II; these affinities were slightly lower than those found in mitochondrial membrane preparations used as the starting material for solubilization. The rank order of potency to inhibit [3H]Ro5-4864 binding in both subpopulations was PK 11195 greater than Ro5-4864 greater than diazepam greater than clonazepam, in connection with the pharmacological specificity of membrane-associated peripheral-type benzodiazepine binding sites. These studies provide direct biochemical evidence that the recognition sites for benzodiazepines and isoquinoline carboxamides cofractionate in unison with the 17-kD PKBS protein, demonstrating an intimate relationship between this protein and the binding domains for peripheral-type benzodiazepine ligands.
Assuntos
Glândulas Suprarrenais/metabolismo , Benzodiazepinonas/metabolismo , Isoquinolinas/metabolismo , Receptores de GABA-A/metabolismo , Glândulas Suprarrenais/efeitos dos fármacos , Marcadores de Afinidade , Animais , Sítios de Ligação , Ligação Competitiva , Células Cultivadas , Fracionamento Químico , Convulsivantes/metabolismo , Mitocôndrias/metabolismo , Ensaio Radioligante , Ratos , Ratos EndogâmicosRESUMO
The multiplicity and complexity of secondary injury processes following brain trauma in vivo make it difficult to elucidate the roles of specific injury mechanisms. As with other areas of CNS injury, such as ischemia, this has led to the development of in vitro models. Here we describe a new trauma model, in which standardized trauma is delivered to neuronal/glial cultures using a special mechanical device that produces concentric circular cuts in the cell layer. Changes in the number of circles (from 1 to 6) allows variation of injury severity. Comparison studies of cell death induced by such trauma in glial and neuronal/glial cultures demonstrated that glial cells are relatively resistant to this injury, and that the cell death after trauma to neuronal/glial cultures reflects primarily neuronal death. Consistent with other in vivo and in vitro studies, glutamate receptor antagonists MK 801 and MCPG were neuroprotective. Thus, this model appears useful for studying glutamatergic mechanisms involved in secondary injury, and may prove useful for evaluating certain pharmacological strategies for CNS trauma.
Assuntos
Lesões Encefálicas/fisiopatologia , Córtex Cerebral/lesões , Modelos Animais de Doenças , Neuroglia/metabolismo , Neurônios/metabolismo , Receptores de Glutamato/fisiologia , Animais , Lesões Encefálicas/patologia , Estudos de Casos e Controles , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Células Cultivadas , Córtex Cerebral/fisiopatologia , Técnicas de Cocultura , Estudos Transversais , Antagonistas de Aminoácidos Excitatórios/farmacologia , L-Lactato Desidrogenase/análise , Modelos Lineares , Estudos Longitudinais , Degeneração Neural/fisiopatologia , Neuroglia/patologia , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Índices de Gravidade do TraumaRESUMO
We have used an in vitro trauma model to examine the effects of modulation of group III metabotropic glutamate receptors (mGluR) on post-traumatic neuronal cell death. Rat cortical neuronal/glial cultures were subjected to standardized mechanical injury using a punch that delivers 28 parallel cuts to 96-well culture plates, resulting in approximately 50% neuronal cell loss in untreated cultures. RT-PCR demonstrated expression of mRNA for mGluR4, mGluR6, mGluR7, and mGluR8 in uninjured cultures as well as in adult rat brain. Treatment with the group III agonists L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) or L-serine-O-phosphate (L-SOP) resulted in dose-dependent neuroprotection. In contrast, treatment with the group III antagonists alpha-methyl-AP4 (MAP4) or (RS)-alpha-methylserine-O-phosphate (MSOP) caused dose-dependent exacerbation of injury, which was significantly attenuated by L-AP4 or L-SOP. The neuroprotective actions of L-AP4 or L-SOP were markedly reduced by the cyclic AMP analog 8-CPT-cAMP (500 microm), which by itself had no effects at this concentration. Moreover, treatment with L-AP4 or L-SOP reduced basal cyclic AMP levels. Treatment with the NMDA antagonist MK 801 decreased post-traumatic cell death by 45% at optimal concentrations; combined treatment with MK 801 and group III agonists showed a significant enhancement of neuroprotection as compared to treatment with the NMDA antagonist alone. Our findings indicate a clear neuroprotective action for group III agonists in this model and suggest that group III mGluR are endogenously activated in response to trauma. The neuroprotective effects of group III agonists appear to result in part from modulation of adenylyl cyclase activity and are additive to those of an NMDA receptor antagonist.
Assuntos
Fármacos Neuroprotetores/uso terapêutico , Sistema Nervoso Periférico/lesões , Receptores de Glutamato Metabotrópico/fisiologia , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacologia , AMP Cíclico/fisiologia , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , L-Lactato Desidrogenase/sangue , Sistema Nervoso Periférico/enzimologia , Reação em Cadeia da Polimerase , Gravidez , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidoresRESUMO
A stoichiometric analysis of N-methyl-D-aspartate (NMDA) receptor binding was conducted using [3H]dizocilpine, [3H]dichlorokynurenic acid and [3H]CGP39653, and membranes from various brain regions of rats. The ratio of the density of [3H]CGP39653 binding to [3H]dizocilpine binding was > 1 in frontal cortex and hippocampus, approximately 1 in striatum and spinal cord and < 1 in cerebellum. When [3H]dichlorokynurenic acid binding was compared with [3H]dizocilpine binding, the ratios were > 1 in frontal cortex, hippocampus and striatum, 3-4 in cerebellum, and approximately 2 in spinal cord. These observations suggest that a single channel complex may have more than one binding site for NMDA and/or glycine and that the stoichiometry between the binding domains of the NMDA receptor varies regionally.
Assuntos
Química Encefálica/fisiologia , Encéfalo/anatomia & histologia , Receptores de N-Metil-D-Aspartato/metabolismo , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacocinética , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Química Encefálica/efeitos dos fármacos , Maleato de Dizocilpina/farmacocinética , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Técnicas In Vitro , Cinética , Ácido Cinurênico/análogos & derivados , Ácido Cinurênico/farmacocinética , Ácido Cinurênico/farmacologia , Masculino , Proteínas do Tecido Nervoso/metabolismo , Ensaio Radioligante , Ratos , Ratos Endogâmicos F344 , Receptores de Glicina/efeitos dos fármacos , Receptores de Glicina/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
The potential interaction between group I metabotropic glutamate receptors (mGluR) and NMDA receptors in mediating of post-traumatic neuronal death was studied using an in vitro trauma model. Treatment with group I mGluR antagonists provided significant neuroprotection either in the presence or absence of an NMDA receptor antagonist. In contrast, treatment with a group I mGluR agonist alone significantly exacerbated injury; this exacerbation was significantly, but incompletely, reduced in the presence of an NMDA receptor antagonist. These findings are consistent with the conclusion that the effects of group I mGluR activation on post-traumatic cell death are mediated only in part through NMDA receptor modulation and suggest that group I mGluR antagonists may have important therapeutic potential.
Assuntos
Lesões Encefálicas , Morte Celular/fisiologia , Maleato de Dizocilpina/farmacologia , Neuroglia/fisiologia , Neurônios/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Animais Recém-Nascidos , Morte Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiologia , Técnicas de Cocultura , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Indanos/farmacologia , L-Lactato Desidrogenase , Modelos Neurológicos , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Resorcinóis/farmacologiaRESUMO
Several compounds, such as epibatidine, A-85380, and their analogs, have been identified recently as nAChR ligands whose affinities lie in the low picomolar range. Accurate measurement of such high affinities is fraught with certain technical difficulties, which may account for the inconsistency of previously reported affinities of epibatidine, ranging from 4 to 60 pM. Here, we demonstrate that (+/-)-[3H]epibatidine (1-500 pM) binds to a single population of sites in rat brain with KD of 8 +/- 2 pM. This affinity was confirmed in both kinetic experiments and competition assays with (+/-)-[3H]epibatidine and (-)-[3H]cytisine, which were performed under experimental conditions developed specifically for ligands with subnanomolar affinities. Variations from these conditions decreased the observed affinities.
Assuntos
Encéfalo/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Agonistas Nicotínicos/metabolismo , Piridinas/metabolismo , Alcaloides/metabolismo , Animais , Azocinas , Ligação Competitiva , Técnicas In Vitro , Cinética , Ligantes , Masculino , Membranas , Quinolizinas , Ensaio Radioligante , Ratos , Ratos Endogâmicos F344 , Receptores Colinérgicos/metabolismo , TemperaturaRESUMO
5-[125I]iodo-3-(2(S)-azetidinylmethoxy)pyridine ([125I]5-I-A-85380) was evaluated in the mouse as a potential in vivo imaging ligand for central nicotinic acetylcholine receptors (nAChRs). After i.v. administration of [125I]5-I-A-85380, peak brain levels of radioactivity were measured within 1 h and declined slowly over 4 h. [125I]5-I-A-85380 binding was saturable, and both its pharmacology, based upon inhibition studies, and its pattern of accumulation in brain regions having high nAChR densities were consistent with an interaction at alpha4beta2 nAChR agonist binding sites. The thalamus:cerebellum radioactivity ratio, a measure of specific labeling, reached 37. Therefore, radiolabeled 5-I-A-85380 has excellent potential as an imaging radiotracer for nAChRs, particularly with single photon emission computed tomography, when 123I is incorporated into the molecule.
Assuntos
Azetidinas/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Autorradiografia , Azetidinas/farmacocinética , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Antagonistas Colinérgicos/farmacologia , Radioisótopos do Iodo , Ligantes , Masculino , Camundongos , Ensaio Radioligante , Convulsões/induzido quimicamente , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]F-A-85380), a ligand for nicotinic acetylcholine receptors (nAChRs) was evaluated in an in vitro binding assay with membranes of rat brain and in vivo by PET in Rhesus monkey brain. The ligand has high affinity for alpha4beta2 nAChRs (K(D)=50 pM), crosses the blood-brain barrier, and distributes in the monkey brain in a pattern consistent with that of alpha4beta2 nAChRs. The specific/non-specific binding ratio increased steadily, reaching a value of 3.3 in the thalamus at 4 h. The specific binding of 2-[18F]F-A-85380 was reversed by cytisine. These results, in combination with the data demonstrating low toxicity of 2-[18F]F-A-85380, indicate that this ligand shows promise for use with PET in human subjects.
Assuntos
Azetidinas , Piridinas , Compostos Radiofarmacêuticos , Receptores Nicotínicos/metabolismo , Tomografia Computadorizada de Emissão , Alcaloides/farmacologia , Animais , Azetidinas/antagonistas & inibidores , Azetidinas/metabolismo , Azetidinas/farmacocinética , Azocinas , Cerebelo/metabolismo , Córtex Cerebral/metabolismo , Ligantes , Macaca mulatta , Piridinas/antagonistas & inibidores , Piridinas/metabolismo , Piridinas/farmacocinética , Quinolizinas , Compostos Radiofarmacêuticos/antagonistas & inibidores , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Tálamo/metabolismo , Fatores de TempoRESUMO
Nicotinic acetylcholine receptors (nAChRs) mediate a variety of brain functions. Findings from postmortem studies and clinical investigations have implicated them in the pathophysiology and treatment of Alzheimer's and Parkinson's diseases and other CNS disorders (e.g. Tourette's syndrome, epilepsy, nicotine dependence). Therefore, it ultimately might be useful to image nAChRs noninvasively for diagnosis, for studies on how changes in nAChRs might contribute to cerebral disorders, for development of therapies targeted at nAChRs, and to monitor the effects of such treatments. To date, only (S)-(-)-nicotine, radiolabeled with 11C, has been used for external imaging of nAChRs in human subjects. Since this radiotracer presents drawbacks, new ligands, with more favorable properties, have been synthesized and tested. Three general classes of compounds, namely, nicotine and its analogs, epibatidine and related compounds, and 3-pyridyl ether compounds, including A-85380, have been evaluated. Analogs of A-85380 appear to be the most promising candidates because of their low toxicity and high selectivity for the alpha4beta2 subtype of nAChRs.
Assuntos
Encéfalo/diagnóstico por imagem , Doenças Neurodegenerativas/diagnóstico por imagem , Nicotina/análogos & derivados , Receptores Nicotínicos/fisiologia , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada de Emissão , Animais , Encéfalo/fisiopatologia , Mapeamento Encefálico , Humanos , Doenças Neurodegenerativas/fisiopatologiaRESUMO
The radiochemical syntheses of 5-[125I]iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-[125I]-iodo-A-85380, [125I]1) and 5-[123I]-iodo-A-85380, [123I]1, were accomplished by radioiodination of 5-trimethylstannyl-3-((1-tert-butoxycarbonyl-2(S)-azetidinyl)metho xy)pyridine, 2, followed by acidic deprotection. Average radiochemical yields of [125I]1 and [123I]1 were 40-55%; and the average specific radioactivities were 1,700 and 7,000 mCi/mumol, respectively. Binding affinities of [125I]1 and [123I]1 in vitro (rat brain membranes) were each characterized by a Kd value of 11 pM. Preliminary in vivo assay and ex vivo autoradiography of mouse brain indicated that [125I]1 selectively labels nicotinic acetylcholine receptors (nAChRs) with very high affinity and specificity. These studies suggest that [123I]1 may be useful as a radioligand for single photon emission computed tomography (SPECT) imaging of nAChRs.
Assuntos
Azetidinas/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Autorradiografia , Azetidinas/farmacocinética , Encéfalo/metabolismo , Estudos de Avaliação como Assunto , Radioisótopos do Iodo , Masculino , Camundongos , Estrutura Molecular , Radioquímica , Ensaio Radioligante , Ratos , Ratos Endogâmicos F344 , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
A novel positron emission tomography (PET) radiotracer, 6-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (6-[18F]fluoro-A-85380, 6-[18F]FA) was synthesized by a no-carrier-added fluorination. In vitro 6-[18F]FA bound to nicotinic acetylcholine receptors (nAChRs), with very high affinity (Kd 28 pM). In PET studies, 6-[18F]FA specifically labeled central nAChRs in the brain of the Rhesus monkey and demonstrated highest levels of accumulation of radioactivity in brain regions enriched with the alpha4beta2 subtype of nAChR. 6-[18F]FA exhibited a target-to-non-target ratio (estimated as radioactivity in the thalamus to that in the cerebellum) of binding in primate brain similar to that previously determined for a labeled analog of epibatidine, [18F]FPH. In contrast to [18F]FPH, the novel tracer is expected to exhibit substantially less toxicity. Thus, the novel radioligand, 6-[18F]FA, appears to be a suitable candidate for imaging nAChRs in human brain.
Assuntos
Azetidinas , Encéfalo/diagnóstico por imagem , Radioisótopos de Flúor , Receptores Nicotínicos/análise , Tomografia Computadorizada de Emissão , Animais , Azetidinas/síntese química , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Macaca mulatta , Masculino , Ratos , Ratos Endogâmicos F344 , Distribuição TecidualRESUMO
The distribution and kinetics of 5-[123I]iodo-A-85380, a novel ligand for brain nicotinic acetylcholine receptors (nAChRs), were evaluated in the Rhesus monkey using single photon emission computed tomography (SPECT). Peak levels of radioactivity were measured in brain at 90 min after injection of the tracer. Accumulation of radioactivity was highest in the thalamus, intermediate in the frontal cortex and basal ganglia, and lowest in the cerebellum. The ratio of specific to nonspecific binding (V3") in the thalamus, estimated from the (thalamic-cerebellar)/cerebellar radioactivity ratio, reached a value of 6 at 4 h post-injection. Specific binding was reduced by subcutaneous injection of 1 mg/kg cytisine at 2.25 h after injection of radiotracer. At 2.5 h after cytisine administration, radioactivity in the thalamus was reduced by 84%, in the frontal cortex, by 76%, and in the basal ganglia, by 57% of the level measured at the time of cytisine administration, demonstrating that the binding was reversible. On the basis of these findings, together with other data indicating high affinity, receptor subtype selectivity, low nonspecific binding and lack of toxicity in animals, 5-[123I]iodo-A-85380 appears to be a promising ligand for SPECT imaging of nAChRs in the human brain.
Assuntos
Azetidinas/farmacocinética , Encéfalo/ultraestrutura , Radioisótopos do Iodo , Compostos Radiofarmacêuticos/farmacocinética , Receptores Nicotínicos/metabolismo , Animais , Azetidinas/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Macaca mulatta , Masculino , Compostos Radiofarmacêuticos/metabolismo , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
A study of 21 schizophrenic patients and 21 normal donors in one experiment, conducted on a pool or erythrocytes in 18 chickens with the use of a double blind method, confirmed the previously obtained data of the stimulant action of plasma in schizophrenic patients on the uptake of tryptophan by chicken erythrocytes. It was demonstrated, that the plasma at the same time evokes an increase of cytoplasmatic enzymes (lactate dehydrogenase and myokynase). The authors studied the correlations between the influence of plasma on the tryptophan uptake and the release of hemoglobin from the erythrocytes and its concentration in the incubation medium. The data also demonstrate the parameters of functions describing the first correlation and that it has a nonmonotonous character. The problem of the connection between the plasma action on the tryptophane uptake and its hemolytic activing is discussed.
Assuntos
Eritrócitos/metabolismo , Soros Imunes/farmacologia , Esquizofrenia/sangue , Triptofano/metabolismo , Adenilato Quinase/metabolismo , Adulto , Animais , Galinhas/sangue , Creatina Quinase/metabolismo , Eritrócitos/enzimologia , Feminino , Hemólise , Humanos , L-Lactato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
The nature of inhibitors of [3H]-diazepam (D) specific binding (SB) was studied in 2 fractions of acidic extract from bovine brain cortex. Preparative high-performance liquid chromatography (HPLC), mass spectrometry, UV and IR techniques identified hypoxanthine and inosine as inhibitors of SB D. These substances may participate in the neuronal activity control which is in part mediated by the benzodiazepine receptors.
Assuntos
Ansiolíticos/antagonistas & inibidores , Córtex Cerebral/metabolismo , Receptores de GABA-A/metabolismo , Animais , Ansiolíticos/farmacocinética , Bovinos , Cromatografia Líquida de Alta Pressão , Diazepam/antagonistas & inibidores , Diazepam/farmacocinética , Hipoxantina , Hipoxantinas/análise , Hipoxantinas/isolamento & purificação , Hipoxantinas/metabolismo , Inosina/análise , Inosina/isolamento & purificação , Inosina/metabolismo , Masculino , Espectrometria de Massas , Ensaio Radioligante , Receptores de GABA-A/efeitos dos fármacos , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
High-performance liquid chromatography, UV spectrometry and mass spectrometry have established that tablets of sibazon and seduxen contained equal quantities of pharmacologically active component diazepam. Radioligand assays revealed the diazepam blood serum levels twice as high 30 to 45 min after oral administration of seduxen than those after sibazon intake (p. less than 0.05). These differences were no more detectable after 2 to 3 hours. The pharmacokinetic differences could be accounted for by the properties of constituents.
Assuntos
Diazepam/análogos & derivados , Diazepam/farmacocinética , Absorção , Adulto , Fenômenos Químicos , Físico-Química , Diazepam/sangue , Avaliação de Medicamentos , Feminino , Humanos , Masculino , Comprimidos , Fatores de TempoAssuntos
Dopamina/metabolismo , Receptores Dopaminérgicos/metabolismo , Esquizofrenia/metabolismo , Inibidores de Adenilil Ciclases , Animais , Antipsicóticos/farmacologia , Apomorfina/farmacologia , Plaquetas/enzimologia , Encéfalo/metabolismo , Bromocriptina/farmacologia , Antagonistas de Dopamina , Haloperidol/farmacologia , Ácido Homovanílico/metabolismo , Humanos , Metiltirosinas/farmacologia , Ratos , Receptores Dopaminérgicos/análise , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Opioides/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/enzimologia , Membranas Sinápticas/fisiologia , Transmissão Sináptica/efeitos dos fármacosRESUMO
Intraperitoneal injection of parachlorphenylalanine to guinea-pigs leads to an increase in the blood tryptophan content and a reduction of blood serum activity that determines tryptophan cell uptake. Administration of 5-hydroxytryptophan brings about opposing changes in the parameters indicated. The presence of a reverse correlation between variations of tryptophan content and blood serum activity responsible for tryptophan cell uptake, which occur under the effect of substances that change the rate of serotonin synthesis indicates that these factors belong to the united system controlling tryptophan metabolism.
Assuntos
5-Hidroxitriptofano/farmacologia , Fenclonina/farmacologia , Triptofano/sangue , Animais , Proteínas Sanguíneas/metabolismo , Radicais Livres , Cobaias , Ligação Proteica/efeitos dos fármacos , Estimulação QuímicaRESUMO
Chromatography of an acidic extract from bovine brain cortex on a Sephadex G-10 column demonstrated 7 fractions capable of inhibiting specific binding of 3H-diazepam to brain cortex membranes. It was established by ultrafiltration that the molecular weights of the inhibitors were not higher than 5000 dalton. Scatchard analysis of 4 main fractions has revealed a type of inhibition similar to the competitive one. Activity of all the fractions remained unchanged after pronase treatment.