RESUMO
Several cytisine derivatives have been developed in the search for more selective drugs at nicotinic acetylcholine receptors (nAChR). Binding experiments in transfected cell lines showed that the iodination of cytisine in the position 3 of the pyridone ring increased potency at alpha7-nAChR and to a lesser extent at the alpha4beta2 subtypes, both of which are widely expressed in the brain. However, no in vivo studies have been published on this compound. Inhibition curves presented here using wild type, beta2, and beta4-null mutant mice confirm that 3-IC binds to alpha4beta2 *, alpha7 * and alpha3beta4 * receptors with higher affinity than cytisine (asterisk indicates the receptor may contain additional subunits, Lukas et al., 1999). Intraperitoneal injection of 3-iodocytisine (3-IC) induced considerable dose-dependent hypothermia in DBA/2J and C57BL/6J mice. This response was blocked by mecamylamine and partially inhibited by hexamethonium. beta4-null mice displayed significantly less 3-IC-induced hypothermia than wild-type mice, beta2-null mice were somewhat less affected than wild types, while responses of alpha7 *-null mice were similar to wild types. Mice treated chronically with 3-IC display a marked increase in alpha7 * and alpha4beta2 * binding sites determined by radioligand binding in membrane preparations from cerebral cortex and hippocampus. Quantitative autoradiographic analysis of 28 brain regions of mice treated with 3-IC was consistent with the membrane binding, detecting an increase of cytisine-sensitive [(125)I]epibatidine binding sites, while cytisine-resistant [(125)I]epibatidine sites were unchanged. [(125)I]alpha-Bungarotoxin binding sites also exhibited up-regulation. These results give a first evaluation of in vivo consequences of 3-IC as a potent agonist with marked effects on mice.
Assuntos
Alcaloides/farmacologia , Azocinas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Hipotermia/induzido quimicamente , Quinolizinas/farmacologia , Receptores Nicotínicos/metabolismo , Animais , Sítios de Ligação , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipotermia/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Distribuição Aleatória , Receptores Nicotínicos/genética , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Monoamine oxidase-A (MAO-A) [amiflamine (AMF) and 4-methylthioamphetamine (MTA)] and MAO-B (L-deprenyl) inhibitors were found to be cytotoxic in a concentration-dependent manner for RCHT cells derived from adult rat hypothalamus. The cytotoxic effects were increased when the inhibitors were co-incubated with dicoumarol and especially with 25 micro M AMF+100 micro M dicoumarol (2.5-fold; P <0.001). The treatment of RCHT cells solely with AMF induced a marked decrease in the expression of DT-diaphorase mRNA.
RESUMO
The antiinflammatory and antipyretic activities of the petroleum ether extract (PEE), dichloromethane extract (DME) and methanol extract (ME1) of the aerial part of Psoralea glandulosa L. (Papilionaceae) were studied. The bioactivity-guided fractionation of the active extracts yielded the isolation of bakuchiol (Bk) from the petroleum ether as the active compound, cyclobakuchiols A and B (Cbk), and angelicin (Ang) from DME.
Assuntos
Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Plantas Medicinais/química , Psoralea/química , Analgésicos não Narcóticos/isolamento & purificação , Animais , Anti-Inflamatórios não Esteroides/isolamento & purificação , Edema/induzido quimicamente , Edema/prevenção & controle , Éteres , Feminino , Cobaias , Espectroscopia de Ressonância Magnética , Masculino , Metanol , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Coelhos , SolventesRESUMO
Human glutathione transferase M2-2 prevents the formation of neurotoxic aminochrome and dopachrome by catalyzing the conjugation of dopamine and dopa o-quinone with glutathione. NMR analysis of dopamine and dopa o-quinone-glutathione conjugates revealed that the addition of glutathione was at C-5 to form 5-S-glutathionyl-dopamine and 5-S-glutathionyl-dopa, respectively. Both conjugates were found to be resistant to oxidation by biological oxidizing agents such as O(2), H(2)O(2), and O(*-)(2), and the glutathione transferase-catalyzed reaction can therefore serve a neuroprotective antioxidant function.
Assuntos
Benzoquinonas/metabolismo , Di-Hidroxifenilalanina/análogos & derivados , Dopamina/metabolismo , Glutationa Transferase/metabolismo , Indolquinonas , Benzoquinonas/química , Cisteinildopa/análogos & derivados , Cisteinildopa/metabolismo , Di-Hidroxifenilalanina/química , Di-Hidroxifenilalanina/metabolismo , Dopamina/química , Glutationa/metabolismo , Glutationa Transferase/química , Humanos , Indóis/metabolismo , Isoenzimas , Espectroscopia de Ressonância Magnética , Modelos Químicos , Oxirredução , Ligação Proteica , Quinonas/metabolismo , Fatores de TempoRESUMO
(S)-(+)-Boldine (1) was brominated, chlorinated, and iodinated using molecular bromine in acetic acid or N-halosuccinimides in trifluoroacetic acid. Initial halogenation occurs at C-3, followed (in the cases of chlorine and bromine) by the less reactive C-8, to afford 3-haloboldines- and 3,8-dihaloboldines (2-5). Using a 2:1 ratio of N-iodosuccinimide to boldine, however, only the 3-iodo derivative 6 was obtained. Radioligand binding studies of these products showed that halogenation of boldine at C-3 favors affinity for D(1)- (vs D(2)-) dopaminergic receptors, attaining a low nanomolar IC(50) value in the case of 3-iodoboldine (6).
Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Aporfinas/química , Aporfinas/farmacologia , Receptores de Amina Biogênica/antagonistas & inibidores , Acetatos , Animais , Anti-Inflamatórios não Esteroides/isolamento & purificação , Aporfinas/isolamento & purificação , Benzazepinas/farmacologia , Ligação Competitiva/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Cloretos/química , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Racloprida/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacosRESUMO
The dopaminergic and antioxidant properties of pukateine [(R)-11-hydroxy-1,2-methylenedioxyaporphine, PUK], a natural aporphine derivative, were analyzed in the rat central nervous system. At dopamine (DA) D1 ([3H]-SCH 23390) and D2 ([3H]-raclopride) binding sites, PUK showed IC50 values in the submicromolar range (0.4 and 0.6 microM, respectively). When the uptake of tritiated dopamine was assayed by using a synaptosomal preparation, PUK showed an IC50 = 46 microM. In 6-hydroxydopamine unilaterally denervated rats, PUK (8 mg/kg but not 4 mg/kg) elicited a significant contralateral circling, a behavior classically associated with a dopaminergic agonist action. When perfused through a microdialysis probe inserted into the striatum, PUK (340 microM) induced a significant increase in dopamine levels. In vitro experiments with a crude rat brain mitochondrial suspension showed that PUK did not affect monoamine oxidase activities, at concentrations as high as 100 microM. PUK potently (IC50 = 15 microM) and dose-dependently inhibited the basal lipid peroxidation of a rat brain membrane preparation. As a whole, PUK showed a unique profile of action, comprising an increase in extracellular DA, an agonist-like interaction with DA receptors, and antioxidant activity. Thus, PUK may be taken as a lead compound for the development of novel therapeutic strategies for Parkinson disease.
Assuntos
Antioxidantes/farmacologia , Aporfinas/farmacologia , Dopaminérgicos/farmacologia , Dopamina/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Animais , Antioxidantes/uso terapêutico , Aporfinas/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Dopaminérgicos/uso terapêutico , Peroxidação de Lipídeos , Masculino , Microdiálise , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Doença de Parkinson/tratamento farmacológico , Desempenho Psicomotor/efeitos dos fármacos , Ensaio Radioligante , Ratos , Ratos Sprague-DawleyRESUMO
1. Ten racemic beta-alkoxy-beta-phenylethylamines were found to elicit concentration-dependent contraction of the isolated rat thoracic aorta with apparent pD2 values in the 4.56-6.76 range. With one exception, which produces the same maximal contraction (Emax) as serotonin (5-HT), the Emax values attained with these compounds are lower than those produced by either 5-HT or norepinephrine (NE). 2. Pretreatment with either prazosin or ketanserin (10(-8) M) leads in most cases to decreased Emax values and slopes in the dose-response curves. Apparent serotonergic (pD2S) and adrenergic (pD2A) pD2 values going from 4.22 to 6.08 (pD2S) and from 3.87 to 5.27 (pD2A) were calculated from results obtained in the presence of prazosin or ketanserin, respectively. 3. In the 10(-7)-10(-5) M range, and in contrast with the results obtained with the previous compounds, BON [(+/-)-2-(2,5-dimethoxy-4-nitrophenyl)-2-methoxy-ethylamine] behaves as an antagonist to both 5-HT and NE (apparent pA2 = 7.08 and 7.45, respectively) in this preparation.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 1 , Agonistas alfa-Adrenérgicos/farmacologia , Aorta Torácica/efeitos dos fármacos , Fenetilaminas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Alquilação , Animais , Técnicas In Vitro , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The monoamine oxidase (MAO) inhibitory properties of a series of amphetamine derivatives with different substituents at or around the para position of the aromatic ring were evaluated. In in vitro studies in which a crude rat brain mitochondrial suspension was used as the source of MAO, several compounds showed a strong (IC50 in the submicromolar range), selective, reversible, time-independent, and concentration-related inhibition of MAO-A. After i.p. injection, the compounds induced an increase of serotonin and a decrease of 5-hydroxyindoleacetic acid in the raphe nuclei and hippocampus, confirming the in vitro results. The analysis of structure-activity relationships indicates that: molecules with amphetamine-like structure and different substitutions on the aromatic ring are potentially MAO-A inhibitors; substituents at different positions of the aromatic ring modify the potency but have little influence on the selectivity; substituents at the para position such as amino, alkoxyl, halogens, or alkylthio produce a significant increase in the activity; the para-substituent must be an electron donor; bulky groups next to the para substituent lead to a decrease in the activity; substituents located at positions more distant on the aromatic ring have less influence and, even when the substituent is a halogen (Cl, Br), an increase in the activity of the compound is obtained. Finally, the MAO-A inhibitory properties of some of the compounds evaluated are discussed in relation to: (a) potential antidepressant activity, and (b) their reported hallucinogenic, neurotoxic, or anxiolytic effects.
Assuntos
Anfetaminas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Animais , Química Encefálica/efeitos dos fármacos , Ácido Hidroxi-Indolacético/análise , Masculino , Ratos , Serotonina/análise , Relação Estrutura-AtividadeRESUMO
The cytoprotective and anti-inflammatory effects of boldine in an experimental model of acute colitis are reported. The administration of boldine to animals with colitis induced by the intrarectal administration of acetic acid, was found to protect against colonic damage as expressed by major reductions in the extent of cell death, tissue disorganization, and edema. Boldine also reduced the colonic neutrophil infiltration, as measured by the myeloperoxidase activity, but it did not significantly affect tissue lipoperoxides. Boldine was found to preserve the colonic fluid transport, a function otherwise markedly affected in the tissue of acid-treated animals. Results presented here provide experimental evidence supporting new cytoprotective and anti-inflammatory properties of boldine.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Aporfinas/uso terapêutico , Colite/tratamento farmacológico , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Absorção Intestinal/efeitos dos fármacos , Peroxidação de Lipídeos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Serotonergic behavioral responses, effects on motor activity and core temperature, and binding properties of the novel putative anxiolytic amphetamine derivative (+/-)1-(2,5-dimethoxy-4-ethylthio-phenyl)-2-aminopropane (ALEPH-2), were examined in rodents in order to elucidate the mechanism underlying its anxiolytic-like effect. After peripheral administration in rats, ALEPH-2 induced some symptoms of the serotonergic syndrome, e.g. forepaw treading and flat body posture. Additionally, a decrease in motor activity was observed. No significant effects on the number of head shakes were observed after injection, although high inter-subject variability was noted. Higher doses of ALEPH-2, in the range exhibiting anxiolytic properties (4mg/kg), elicited significant hypothermia in mice. The affinity of the drug for 5-HT2A/2C receptors ([3H]ketanserin sites) was in the nanomolar range (Ki = 173 nM), whereas for 5-HT1A, benzodiazepine sites, and GABAA receptors, the affinity was micromolar of lower. Based on these results the mechanism of action and the anxiolytic-like properties of ALEPH-2 are discussed.
Assuntos
Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , 2,5-Dimetoxi-4-Metilanfetamina/análogos & derivados , 2,5-Dimetoxi-4-Metilanfetamina/administração & dosagem , 2,5-Dimetoxi-4-Metilanfetamina/metabolismo , 2,5-Dimetoxi-4-Metilanfetamina/farmacologia , Análise de Variância , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/metabolismo , Sítios de Ligação , Temperatura Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipotermia/induzido quimicamente , Ketanserina/metabolismo , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de GABA-A/metabolismo , Receptores de GABA-A/fisiologia , Receptores de Serotonina/metabolismo , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/metabolismoRESUMO
6-Bromoflavone, obtained by bromination of flavanone, binds to central benzodiazepine receptors with a Ki=70 nM and has a clear anxiolytic activity in mice, at 0.5 mg/kg i.p. A survey of the structure/affinity relationship for those receptors in a series of natural and synthetic flavonoids is presented.
Assuntos
Marcadores de Afinidade/metabolismo , Ansiolíticos/metabolismo , Flavonoides/metabolismo , Receptores de GABA-A/metabolismo , Marcadores de Afinidade/síntese química , Marcadores de Afinidade/farmacologia , Análise de Variância , Animais , Ansiolíticos/síntese química , Ansiolíticos/farmacologia , Flavonoides/síntese química , Flavonoides/farmacologia , Flunitrazepam/metabolismo , Cinética , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Relação Estrutura-Atividade , Ácido gama-Aminobutírico/farmacologiaRESUMO
Boldine, an aporphine alkaloid, was recently shown by us to exhibit potent antioxidant properties. We report here that boldine concentration-dependently inhibited the peroxidative (accumulation of thiobarbituric acid reactive substances) and lytic damage (trypan blue exclusion and lactate dehydrogenase leakage) to isolated rat hepatocytes induced by tert-butyl hydroperoxide (TBOOH). Boldine (200 micromol/L) fully cytoprotected and completely prevented the peroxidation induced by TBOOH at concentrations equal to or lower than 0.87 mmol/L. However, at a peroxide concentration of 0.91 mmol/L, although boldine completely inhibited lipid peroxidation it largely failed to afford cytoprotection against TBOOH. TBOOH alone (0.83 mmol/L) caused an early (within 60 s) sudden decline of reduced glutathione (by 50%) and an equivalent increase in the levels of oxidized glutathione. Neither of these effects was prevented by the simultaneous addition of a cytoprotective and antioxidant concentration of boldine (200 micromol/L). The delayed addition of boldine to the suspension (after 10 or 20 min), while effectively blocking any further increase in thiobarbituric acid reactive substances, totally failed to prevent the peroxide-induced loss in cell viability. Conversely, preincubation of the hepatocytes with boldine for 150 min (at which time no boldine could be detected in either intra- or extracellular spaces) prevented lipid peroxidation and was as effective in protecting the cells against the damage caused by the subsequent addition of TBOOH as the simultaneous addition of boldine and TBOOH to hepatocytes preincubated for 150 min under control conditions.
Assuntos
Antioxidantes/farmacologia , Aporfinas/farmacologia , Fígado/citologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Glutationa/metabolismo , Peroxidação de Lipídeos , Masculino , Peróxidos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Fatores de Tempo , terc-Butil HidroperóxidoRESUMO
4-Dimethylaminophenethylamine (DMAPEA) was characterized as an MAO substrate. This compound was unaffected by MAO-A, while its oxidation by MAO-B was linear as a function of both time and enzyme concentration, with Km = 5.8 microM and Vmax = 21.2 pmol/min/mg protein, using a crude rat brain mitochondrial suspension as source of MAO. Both DMAPEA and its oxidation product, 4-dimethylaminophenylacetic acid (DMAPAA), can be detected electrochemically at 0.85 V. The high MAO-B affinity and selectivity of DMAPEA, together with its low oxidation potential, make this molecule a unique tool to determine MAO-B activity in a wide variety of tissue preparations using HPLC-ED.
Assuntos
Monoaminoxidase/metabolismo , Fenetilaminas/metabolismo , Animais , Encéfalo/enzimologia , Cromatografia Líquida de Alta Pressão , Clorgilina/farmacologia , Cinética , Masculino , Mitocôndrias/enzimologia , Oxirredução , Fenetilaminas/química , Fenilacetatos/química , Fenilacetatos/metabolismo , Ratos , Selegilina/farmacologiaRESUMO
Boldo (Peumus boldus Mol.), a Chilean tree traditionally employed in folk medicine and recognized as a herbal remedy in a number of pharmacopoeias, mainly for the treatment of liver ailments, has recently been the subject of increasing attention. Boldine, in particular, the major and most characteristic alkaloidal constituent of this plant species, now emerges as its most interesting active principle from the pharmacological viewpoint. The recent demonstration that boldine is an effective antioxidant in both biological and non-biological systems has opened up the perspective of a broad range of uses in medicine and industry. Given the toxicological data on this alkaloid, its antioxidative properties situate it as a potentially useful substance in many disease states featuring free-radical related oxidative injury. This review attempts to cover and discuss the studies conducted over the last four decades on the chemical and pharmacological properties of boldo and its main constituent.
Assuntos
Antioxidantes/farmacologia , Aporfinas/farmacologia , Plantas Medicinais/química , Animais , Antioxidantes/química , Aporfinas/química , Chile , HumanosRESUMO
Two previously undescribed elemanolide esters, the 2-methylpropanoate and 2-methyl-2-propenoate of 11,13-dehydromelitensin, were isolated in the course of a bioassay-guided fractionation from the aerial parts of Centaurea chilensis Hook. et Arn., used traditionally to treat 'gout and rheumatism'. The mixture of both substances exhibits anti-inflammatory activity in the carrageenan-induced paw edema assay.
Assuntos
Anti-Inflamatórios não Esteroides/isolamento & purificação , Benzofuranos/isolamento & purificação , Plantas Medicinais/química , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Benzofuranos/farmacologia , Carragenina , Chile , Edema/induzido quimicamente , Edema/patologia , Feminino , Cobaias , Masculino , Extratos Vegetais/análiseRESUMO
Four amphetamine derivatives bearing a methylenedioxy group at positions 3 and 4 of the benzene ring and differing in their substitution at C(6) were studied by differential pulse voltammetry in aqueous media. These experiments showed a single oxidation peak for the C(6)-H, -Br and -Cl compounds, while the C(6)-NO(2) analogue was not oxidized. The oxidation peak is interpreted as due to the removal of one electron from the aromatic electrophore with formation of a radical cation stabilized by the dioxole ring. The linear relationship between the peak current and the concentration of the derivatives is appropriate for development of a quantitative method for their determination. pK' values were determined using both electrochemical and spectrophotometric methods.
RESUMO
Boldine, in low micromolar concentrations, was able to prevent brain homogenate autooxidation, the 2,2'-azobis(2-amidinopropane)(AAP)-induced lipid peroxidation of red cell plasma membranes, and the AAP-induced inactivation of lysozyme. These results are indicative of a high reactivity of boldine towards free radicals. The analysis of the boldine effect as a function of incubation times suggests that a metabolite resulting from the interaction of boldine with free radicals also exhibits antioxidant activity, being more efficient than boldine in brain homogenate auto-oxidation and less efficient in lysozyme protection experiments. This behavior may be accounted for in terms of the relative location of the scavengers needed to afford maximal protection.
Assuntos
Antioxidantes/química , Aporfinas/química , Peroxidação de Lipídeos , Amidinas/farmacologia , Animais , Aporfinas/farmacologia , Química Encefálica , Relação Dose-Resposta a Droga , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Cinética , Medições Luminescentes , Masculino , Muramidase/antagonistas & inibidores , Consumo de Oxigênio , Ratos , Ratos EndogâmicosRESUMO
The major components of the acid fraction of the leaves and tender stems of Aristolochia chilensis Miers are aristolochic acids I and Ia. Aristolochic acid Ia has been isolated from plant material for the fïrst time, and its PMR spectrum is discussed.