RESUMO
Using the acylation reaction with tosyl chloride of N-aminopropyl analogues of tacrine and its cyclic homologues with different size of the aliphatic cycle (5-8), we synthesized a number of new derivatives of p-toluenesulfonamide. It is shown that the synthesized hybrid compounds of tacrine and p-toluenesulfonamide are effective inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with the preferential inhibition of BChE. They also displace propidium from the peripheral anionic site of the electric eel AChE (Electrophorus electricus). The characteristics of the efficiency and selectivity of cholinesterase inhibition by the test compounds were confirmed by the results of molecular docking.
Assuntos
Acetilcolinesterase/química , Butirilcolinesterase/química , Inibidores da Colinesterase , Electrophorus , Proteínas de Peixes , Sulfonamidas/química , Tacrina/química , Tolueno/análogos & derivados , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Proteínas de Peixes/antagonistas & inibidores , Proteínas de Peixes/química , Tolueno/químicaRESUMO
Conjugates of tacrine with 1,2,4-thiadiazole derivatives were synthesized for the first time. Their esterase profile and effects on the key NMDA receptor-binding sites as well as antioxidant activity were investigated. The obtained compounds effectively inhibited cholinesterases (with a predominant effect on butyrylcholinesterase), simultaneously blocked two NMDA receptor-binding sites (allosteric and intrachannel sites, and exhibited a high radical-scavenging activity. Our study shows that the obtained compounds are promising to design drugs for the treatment of Alzheimer's disease and other multifactorial neurodegenerative diseases.
Assuntos
Antioxidantes/farmacologia , Inibidores da Colinesterase/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tacrina/química , Tiadiazóis/química , Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Humanos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Tacrina/farmacologia , Tiadiazóis/farmacologiaRESUMO
Analysis of antioxidant activity of synthesized selenourea derivatives showed that N,N'-substituted selenoureas inhibited Fe(III)-induced LPO in rat brain homogenate. On the other hand, oxygen- and sulfur-containing analogs exhibited no antioxidant activity or even slight prooxidant activity. Intramolecular alkylation of selenium atom also led to loss of antioxidant activity. Thus, antioxidant activity of the compounds was due to the presence of a nonalkylated selenium atom in N,N'-substituted selenourea analogs.
Assuntos
Antioxidantes/farmacologia , Compostos Férricos/farmacologia , Compostos Organosselênicos/farmacologia , Ureia/análogos & derivados , Animais , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Ureia/farmacologiaRESUMO
Among 3-(2-aminopropyl)-1,2,4-thiadiazole derivatives contatining substitution-ready secondary amino group and exhibiting cytotoxic towards rat C 6 glioma cells three compounds with LD 50 values ranged from 6 to 48 мM were chosen. For these compounds amides with docosahexaenoic acid were synthetised and their cytotoxic activity was studied. It was shown that, although docosahexaenoic acid itself was not toxic for C 6 glioma cells, its addition to the amino derivatives of 1,2,4-thiadiazole increased or decreased resultant cytotoxicity. The effect depended on the structure of 1,2,4-thiadiazole substituents. The obtained data show that the acylation of cytotoxic compounds with docosahexaenoic acid does not necessarily lead to the increase of their activity, but sometimes can inactivate a compound. This fact should be taken into account, especially in the case of anti-cancer drug development.
Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Ácidos Docosa-Hexaenoicos/química , Neuroglia/efeitos dos fármacos , Tiadiazóis/farmacologia , Amidas/síntese química , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Citotoxinas/síntese química , Desenho de Fármacos , Concentração Inibidora 50 , Neuroglia/patologia , Ratos , Relação Estrutura-Atividade , Tiadiazóis/síntese químicaRESUMO
The effect of derivatives of arachidonic and docosahexaenoic acids on AMPA receptors in Purkinje cells from the rat cerebellum was studied using the patch-clamp electrophysiological method. It was shown that derivatives of arachidonic acid-arachidonoyl dopamine and docosahexaenoic acid-docosahexaenoyl dopamine and ester of docosahexaenoic acid with ethylene glycol in nanomolar concentrations effectively potentiated the ionic currents caused by activation of AMPA receptors of kainic acid. Ester of docosahexaenoic acid with nitroethylene glycol blocked AMPA receptors, and anandamide (ethanolamide of arachidonic acid) was not effective. A behavioral test showed that docosahexaenoyl dopamine in doses of 0.1-20 mg/kg had no effect on the learning and memory abilities of the animals tested.
Assuntos
Ácidos Araquidônicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Células de Purkinje/efeitos dos fármacos , Receptores de AMPA/metabolismo , Animais , Ácidos Araquidônicos/química , Células Cultivadas , Ácidos Docosa-Hexaenoicos/química , Relação Dose-Resposta a Droga , Masculino , Potenciais da Membrana/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Células de Purkinje/metabolismo , Ratos , Tempo de Reação/efeitos dos fármacosRESUMO
Glycerol esters 1,3-dinitrates of the cyclooxygenase metabolites of natural prostaglandin 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors, were synthesized for the first time. Four methods of synthesis of these esters were developed via the activation of a carboxyl group and their chemical and pharmacological properties were investigated. The esters exhibit a more selective pharmacological spectrum of activities in comparison with the corresponding natural prostaglandins: some types of myotropic activity were enhanced, while others were loosened. 1,3-dinitroglycerol esters act as vasodilators, whereas the majority of natural prostaglandins act as vasoconstrictors. The observed changes result from the introduction of an NO-releasing fragment into prostaglandin molecule.
Assuntos
Ácidos Araquidônicos/química , Ácidos Araquidônicos/síntese química , Glicerol/análogos & derivados , Nitratos/química , Nitratos/síntese química , Prostaglandina-Endoperóxido Sintases/química , Ácidos Araquidônicos/metabolismo , Ésteres , Glicerol/síntese química , Glicerol/química , Glicerol/metabolismo , Nitratos/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismoRESUMO
Methods of synthesis of prostaglandin fluorides were developed and their properties were investigated. These compounds were shown to be convenient synthetic precursors for obtaining esters and amides of natural prostaglandins and their fluorodeoxy analogues.
Assuntos
Anidridos/síntese química , Flúor , Prostaglandinas/síntese química , Anidridos/química , Ésteres , Prostaglandinas/químicaAssuntos
Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/farmacologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Animais , Cálcio/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
We studied the effect of prostaglandins on presynaptic NMDA receptors. Prostaglandin E2 inhibited NMDA-induced (45)Ca2+ uptake by synaptosomes in low concentrations (IC50 approximately 10 microM), but potentiated it in higher concentrations. Prostaglandin D2 increased (45)Ca2+ uptake by synaptosomes during stimulation of NMDA receptors. Our results indicate that prostaglandins D2 and E2 modulate function of presynaptic NMDA receptors.
Assuntos
Córtex Cerebral/metabolismo , Dinoprostona/metabolismo , Terminações Pré-Sinápticas/metabolismo , Prostaglandina D2/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Córtex Cerebral/citologia , Ratos , Ratos Wistar , Sinaptossomos/metabolismoRESUMO
O-Nitration of the allylic hydroxyl group in prostaglandins and the synthesis of 15-O-nitrates of 11-deoxyprostaglandin E1 and its methyl ester are described for the first time.
Assuntos
Alprostadil/análogos & derivados , Éteres Metílicos/síntese química , Nitratos/síntese química , Alprostadil/química , Éteres Metílicos/química , Nitratos/químicaAssuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/metabolismo , Receptores de AMPA/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Ácidos Docosa-Hexaenoicos/química , Técnicas In Vitro , Ácido Caínico/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Ratos , Receptores de AMPA/metabolismoRESUMO
A series of six new synthetic dinitroglycerol esters of fatty acids on the human platelet aggregation was studied in vitro. Inclusion of the dinitroglycerol moiety into the molecule of arachidonic acid deprived this acid from pro-aggregant activity. All six compounds produced moderate (dose-dependent) inhibition of the platelet aggregation process induced by arachidonic acid (1 x 10(-3) M). Platelet aggregation was most significantly affected by dinitroglycerol esters of arachidonic and docosahexaenoic acids. This is probably explained by the influence of these esters on the oxidative metabolism of arachidonic acid to eicosanoids playing the role of proaggregants. In the presence of vessel wall (rat aorta fragments), dinitroglycerol esters of arachidonic and docosahexaenoic acids incubated with platelets (5 min, 37 degrees C) significantly reduced their aggregation induced by arachidonic acid (1 x 10(-3) M) or docosahexaenoic acid (1 x 10(-5) M) under the conditions of endothelial cyclooxygenase suppressed by acetylsalicylic acid (10 mg/ml). The pronounced antiaggregant effect of the synthetic dinitroglycerol esters studied is probably related to their ability to act as NO donors suppressing the activity of thrombocytes (provided that the NO production activity is present in the system).
Assuntos
Ácidos Graxos/farmacologia , Glicerol/análogos & derivados , Glicerol/farmacologia , Nitrocompostos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Animais , Aorta , Inibidores de Ciclo-Oxigenase/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Ésteres , Ácidos Graxos/química , Glicerol/química , Humanos , Técnicas In Vitro , Nitrocompostos/química , Ratos , Relação Estrutura-AtividadeRESUMO
The interaction of organic nitrates (nitroethyleneglycol, dinitroglycerol, and their esters with arachidonic acid) with oxyhemoglobin and methemoglobin has been studied. Addition of nitroethyleneglycol and dinitroglycerol to oxyhemoglobin is accompanied by a modest but significant increase in oxidation rate of the heme protein to the high-spin ferri-form--methemoglobin. Arachidonoylglycerol dinitrate exerts a similar but more pronounced effect on hemoglobin: a molar excess of this dinitrate induces the transformation of a significant portion of oxyhemoglobin to methemoglobin, whereas arachidonoylnitroethyleneglycol is inactive. Arachidonoylglycerol dinitrate also induces changes in the spectral characteristics of methemoglobin; this may be due to disintegration of the methemoglobin with the loss of heme. The data demonstrate that some organic nitrates can interact with hemoglobin; this should be taken into account when using the oxyhemoglobin technique for measuring nitric oxide generation from these compounds.
Assuntos
Etilenoglicóis/química , Hemoglobinas/química , Nitroglicerina/análogos & derivados , Humanos , Nitroglicerina/química , Espectrofotometria UltravioletaRESUMO
(+/-)-15-Fluoro-11,15-dideoxyprostaglandin E1 and its methyl and ethyl esters were synthesized. Dehydroxyfluorination reaction (+/-)-11-deoxyprostaglandin E1 esters with various reagents based on SF4 was studied. Along with the target 15-fluorides (mixtures of alpha- and beta-epimers), products of allylic shift and dehydration in a ratio dependent on the fluorination agent were shown to be formed. With a morpholinotrifluorosulfuran-tris(morpholine)sulfonium trimethyldifluorosilicate mixture, the maximal excess (70%) of one of the 15-fluoro epimers was achieved. Possible mechanisms of dehydroxyfluorination of (+/-)-11-deoxyprostaglandin E1 esters with dialkylaminoflluorosulfurans were proposed. Methyl esters of 15-alpha-fluoro- and 15-beta-fluoro-11,15-dideoxyprostaglandin E1 exhibited moderate antiaggregation activity in rabbit platelet tests.
Assuntos
Alprostadil/análogos & derivados , Inibidores da Agregação Plaquetária/síntese química , Alprostadil/síntese química , Alprostadil/química , Alprostadil/farmacologia , Animais , Técnicas In Vitro , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Coelhos , EstereoisomerismoRESUMO
The effects of fluorodeoxy prostanoids on platelet aggregability were studied. It was shown that introduction of fluorine into positions 9, 11 or 15 of prostaglandin F2 alpha led to enhanced proaggregation activity. The most active compound among fluorodeoxy analogs was 15-fluoro derivative; bisfluoro analog was moderately active, and 11-fluoro compound had the least activity. In the group of fluorodeoxy prostaglandins E2, a contrary effect was registered. Thus, the most active compound was 1-fluoride and the least, 15-fluoride. The incorporation of fluorine into position 15 of prostacyclin led to insignificantly lower antiaggregatory activity just as this modification of 6-keto-prostaglandin F1 alpha was accompanied by a dramatic increase in its ability to inhibit platelet aggregation.
Assuntos
Agregação Plaquetária/efeitos dos fármacos , Prostaglandinas Sintéticas/farmacologia , Difosfato de Adenosina/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Coelhos , Relação Estrutura-AtividadeRESUMO
The effect of exchange of 15-hydroxyl for fluor on biological activity of PGF2 alpha and PGE2 on isolated smooth muscles of different organs has been studied. The exchange leads to significant increase in contractile (100-fold) and relaxation (1000-fold) activity of PGF2 alpha on smooth respiratory muscles. At the same time, the effect of 15-fluor-15-deoxyprostaglandin F2 alpha on smooth muscles of intestinal and vascular tracts did not differ from that of PGF2 alpha. Similar modification of PGE2 led to the decrease (10-fold) both in contractile and relaxation activity on all studied types of smooth muscles. The data obtained have been discussed within the boundaries of prostanoid receptor classification (Kennedy, 1982). Fluor derivative of PGF2 alpha may be used for pharmacological differentiation of EP-receptors.
Assuntos
Dinoprosta/análogos & derivados , Dinoprostona/análogos & derivados , Músculo Liso/efeitos dos fármacos , Animais , Cricetinae , Dinoprosta/farmacologia , Dinoprostona/farmacologia , Relação Dose-Resposta a Droga , Cobaias , Técnicas In Vitro , Masculino , Mesocricetus , Contração Muscular/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
In a search for stable thromboxanomimetics the action of 11-fluoro-11-deoxyprostaglandin F2 alpha (11-fluoro-PGF2 alpha) on the aggregatory properties of platelets and the tone of the vascular, respiratory and gastrointestinal smooth muscles was studied. It was found that 11-fluoro-PGF2 alpha, in contrast to PGF2 alpha, induces platelet aggregation and exhibits a high activity with respect to smooth muscles sensitive to thromboxane A2 alpha (TXA2) and a low activity for smooth muscles sensitive to PGF2 alpha 9-11-epoxyimino-PGH2 (a specific antagonist of TXA2 receptors) competitively blocked the action of 11-fluoro-PGF2 alpha on vascular smooth muscles. Thus, 11-fluoro-PGF2 exhibits properties of a thromboxanomimetic that makes it possible to propose it for modelling TXA2-induced biological effects.