RESUMEN
The influence of physical and chemical properties of some sites of transmembrane receptor domains on the receptors ability to interact with nonspecific antagonists was investigated mathematically. The properties of sites located in 3rd and 7th transmembrane domains are most likely to explain pharmacological characteristics of the receptors. The possibility of receptor blocking by nonspecific antagonists not by competing with agonists but by influencing the receptor conformation is discussed.
Asunto(s)
Receptores de Amina Biogénica/antagonistas & inhibidores , Animales , Sitios de Unión , Humanos , Ratas , Receptores de Amina Biogénica/química , Receptores de Amina Biogénica/metabolismoRESUMEN
The influence of the tricyclic antidepressants imipramine and ftoracizin on platelet aggregation and smooth muscle contractility was investigated in comparison with action of known smooth muscle relaxant and platelet aggregation inhibitor, papaverine. It has been shown that the tricyclic antidepressants possess potent spasmolytic activity but unlike papaverine have no effect on platelet aggregation. The biochemical mechanisms of the non-specific action of tricyclic antidepressants as well as some other structurally related-drugs are discussed.
Asunto(s)
Antidepresivos Tricíclicos/farmacología , Imipramina/farmacología , Músculo Liso/efectos de los fármacos , Fenotiazinas/farmacología , Agregación Plaquetaria/efectos de los fármacos , Animales , Evaluación Preclínica de Medicamentos , Masculino , Contracción Muscular/efectos de los fármacos , Papaverina/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Ratas , Ratas Wistar , Uréter/efectos de los fármacosRESUMEN
The effect of pH and binding of ten physiologically active compounds (isoproterenol, yohimbine, propranolol, clonidine, phenylephrine, carbachol, tripeptide fMLP, diphenhydramine, chlorpromazine and atropine) on the molecular structure of human serum albumin (HSA) has been studied using the dynamic light scattering. It was found that albumin globule has the most compact configuration (Stokes diameter 59-62 A) at physiological pH 7.4. The changes in pH, both increase to 8.0 and decrease to 5.4, result in the growth of globule size to 72-81 A. At acidic shift of pH an additional peak arises in the correlation spectra caused by the light scattering on the structures with the Stokes diameters of 29-37 A. Those conform to the sizes of the albumin subdomains. The indicated peak is not displayed at basic shift of pH. The interaction with propranolol, clonidine, phenylephrine, carbachol and tripeptide fMLP which hinder adenylate cyclase (AdC) and activate Ca-polyphosphoinositide (Ca-PPI) signaling system of a cell initiates structural rearrangements similar to acidic transitions. Isoproterenol, yohimbine diphenhydramine, chlorpromazine and atropine, which activate AdC and hinder Ca-PPI, cause conformational changes of HSA similar to basic transitions.
Asunto(s)
Albúmina Sérica/química , Albúmina Sérica/metabolismo , Atropina/sangre , Carbacol/sangre , Clorpromazina/sangre , Clonidina/sangre , Difenhidramina/sangre , Humanos , Concentración de Iones de Hidrógeno , Isoproterenol/sangre , Cinética , N-Formilmetionina Leucil-Fenilalanina/sangre , Fenilefrina/sangre , Propranolol/sangre , Unión Proteica , Dispersión de Radiación , Yohimbina/sangreRESUMEN
The report describes the results of a study the effect of pH and binding of six physiologically active compounds (isoproterenol, yohimbine, theophylline, propranolol, clonidine and carbachol) on the molecular structure of human serum albumin (HSA) using dynamic light scattering. It was found that the albumin globule had the most compact configuration (Stokes diameter 59-62A) at physiological pH 7.4. The changes in pH both increased to 8.0 and decreased to 5.4, resulting in the growth of globule size to 72-81A. At acidic shift of pH an additional peak arose in the correlation spectra. This peak was caused by the light scattering on the structures with the Stokes diameters of 29-37A, which conformed to the sizes of the albumin subdomains. The additional peak was not displayed at basic shift of pH. The interaction with propranolol, clonidine and carbachol, which hinder adenylate cyclase (AdC) signaling system of a cell, initiated structural rearrangements similar to acidic transitions. Isoproterenol, yohimbine and theophylline, which activate AdC, caused the conformational changes of HSA similar to basic transitions.
Asunto(s)
Adenilil Ciclasas , Carbacol/farmacología , Clonidina/farmacología , Isoproterenol/farmacología , Propranolol/farmacología , Conformación Proteica , Albúmina Sérica/efectos de los fármacos , Teofilina/farmacología , Yohimbina/farmacología , Carbacol/metabolismo , Clonidina/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Isoproterenol/metabolismo , Propranolol/metabolismo , Albúmina Sérica/química , Albúmina Sérica/metabolismo , Teofilina/metabolismo , Yohimbina/metabolismoRESUMEN
Influence of bioregulators on the phospholipid Langmuir monolayers made of distearoylphosphatidylcholine and its equimolar mixture with dimitrystoylphosphatidylcholine was investigated. The results obtained allow concluding that the presence of physiologically active compounds in the subphase weakens the lipid-lipid interaction and increases the free energy change of air-liquid interface in the case of pure distearoylphosphatidylcholine monolayers, but in the case of mixed monolayers it leads both to the increase and decrease of these parameters. Presence of the dimirystoylphosphatidylcholine molecules with the short fatty acyl chains in the monolayer destabilizes it. This effect is partially compensated by the interaction between lipid and subphase molecules.
Asunto(s)
Dimiristoilfosfatidilcolina/química , Fosfatidilcolinas/química , Adenosina Trifosfato/farmacología , Adyuvantes Inmunológicos/farmacología , Adrenérgicos/farmacología , Aire/análisis , Tampones (Química) , Cloroformo/química , Antagonistas de los Receptores Histamínicos H1/farmacología , N-Formilmetionina Leucil-Fenilalanina/farmacología , Parasimpatolíticos/farmacología , Relación Estructura-Actividad , Termodinámica , Agua/químicaRESUMEN
Effects of some drugs on different levels of phagocytic activity of polymorphonuclear leukocytes (PMNL) of human peripheral blood were studied in vitro. The drugs were found to regulate the phagocytic activity of PMNL. This effect depended on the initial level of PMNL phagocytic activity but not on the drug appurtenance to a certain pharmacological group.
Asunto(s)
Neutrófilos/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Adenosina Trifosfato/farmacología , Agonistas Adrenérgicos/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Atropina/farmacología , Donantes de Sangre , Broncodilatadores/farmacología , Cardiotónicos/farmacología , Ciclofosfamida/farmacología , Diclofenaco/farmacología , Difenhidramina/farmacología , Epinefrina/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Inmunosupresores/farmacología , Técnicas In Vitro , Isoproterenol/farmacología , Ratones , Papaverina/farmacología , Parasimpatolíticos/farmacología , Fenilefrina/farmacología , Propranolol/farmacología , Simpatomiméticos/farmacología , Teofilina/farmacología , Vasodilatadores/farmacologíaRESUMEN
Study on the effects of some drugs on the results of passive hemagglutination test used for the detection of antitetanus antibodies in the blood serum showed that some drugs had a pronounced dose-dependent effect on antibody titers in experiments in vitro with standard antitoxic serum. The possibility of such errors should not be disregarded when assessing the results of the test.
Asunto(s)
Pruebas de Hemaglutinación , Antitoxina Tetánica/análisis , Antitoxina Tetánica/efectos de los fármacos , Tétanos/diagnóstico , Clostridium tetani/inmunología , Errores Diagnósticos , Humanos , Tétanos/inmunologíaRESUMEN
Receptor and transporter of neurotransmitters similarity in ability of ligand-binding makes us consider them to possess the sites of similar structure and physico-chemical characteristics. However direct analysis of amino acid sequences alignment did not allow revealing such sites. For functionally similar proteins that differ in primary structure, the similarity extent is satisfactory estimated as based on physico-chemical properties of individual domain. We have analyzed transmembrane domains of a set of receptors and transporters of choline, norepinephrine, dopamine and serotonin. In our analysis in direction from extracellular border to intracellular one, amino acid sequences of transmembrane domains were divided into fragments each consisting of 4 amino acids. Every fragment was characterized by physico-chemical properties, such as hydrophilicity, hydrophobicity, polarity, etc. Hierarchical cluster analysis in space of the physico-chemical properties of these fragments was performed. As a result we have obtained both heterogeneous clusters, which contained receptor and transporter fragments, and homogeneous clusters which contained only receptor or transporter domains. An analysis of heterogeneous clusters has shown that the 4th, 5th and 6th transmembrane receptor domains and the 2d, 3d and 7th transmembrane transporter helices possess maximum similarity. The results obtained allow one to make a conclusion that these domains take part in formation of the ligand-binding centers.
Asunto(s)
Neurotransmisores/metabolismo , Estructura Terciaria de Proteína , Receptores de Neurotransmisores/química , Animales , Transporte Biológico/fisiología , Fenómenos Químicos , Química Física , Análisis por Conglomerados , Humanos , Membranas/metabolismo , RatasRESUMEN
Effects of chlorpromazine, haloperidol (neuroleptics and calmodulin antagonists), and verapamil on rat platelet aggregation induced by thrombin, on calcium current in snail neurones and on both tonic tension of high potassium contracture and phasic contraction of isolated guinea-pig ureter preparations were studied. Moreover, droperidol, sulpiride and prazosine effects were studied for models of phasic contractility and platelet aggregation. Sulpiride and prazosine were ineffective, verapamil was ineffective on platelet aggregation, while droperidol was the most potent inhibitor of platelet aggregation. These results, the similarity revealed in the blockage of neuronal calcium current by neuroleptics and verapamil, and the potent inhibitory action of haloperidol and chlorpromazine on contractility and aggregation suggest that both phenothiazine and butyrophenone neuroleptics possess some properties of calcium antagonists and may also have intracellular sites of action other than calmodulin.
Asunto(s)
Antipsicóticos/farmacología , Canales de Calcio/fisiología , Clorpromazina/farmacología , Haloperidol/farmacología , Contracción Isométrica/efectos de los fármacos , Músculo Liso/fisiología , Neuronas/fisiología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Animales , Butirofenonas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/efectos de los fármacos , Calmodulina/antagonistas & inhibidores , Droperidol/farmacología , Estimulación Eléctrica , Cobayas , Técnicas In Vitro , Masculino , Músculo Liso/efectos de los fármacos , Neuronas/efectos de los fármacos , Fenotiazinas/farmacología , Prazosina/farmacología , Ratas , Ratas Wistar , Caracoles , Sulpirida/farmacología , Trombina/farmacología , Uréter , Verapamilo/farmacologíaRESUMEN
The effect of the synthetic thrombin substrate (TAME) and three compounds exerting an opposite effect on Ca-PPI and AdC (caffeine, atropine and meta-tolyl derivative of mechlorethamine (TDM)) on hormone-like and catalytic functions of thrombin was studied. It is shown that both TAME and other drugs under test block effectively the thrombin-induced platelet aggregation, as well as protect the active site of the enzyme from denaturation by dithiothreitol. The same compounds inhibit thrombin in thrombin-fibrinogen reaction and platelet 12-lipoxygenase. These data suggest identity of thrombin moieties which determine its enzymatic and hormone-like activities.
Asunto(s)
Alquilantes/farmacología , Araquidonato 12-Lipooxigenasa/efectos de los fármacos , Atropina/farmacología , Cafeína/farmacología , Trombina/efectos de los fármacos , Tosilarginina Metil Éster/farmacología , Animales , Araquidonato 12-Lipooxigenasa/clasificación , Plaquetas/enzimología , Catálisis , Masculino , Ratas , Ratas WistarRESUMEN
The mobility of the rat polymorphonuclear leukocytes (PMNL) has been studied. It was shown, that it is greatly determined by the balance of adenylate cyclase (AdC) and Ca-polyphosphoinositide (Ca-PPI) cell signalling systems. Various compounds whose action on the activity of the signalling systems was previously connected with the membrane receptors, proved to be capable to affect the activity of submembrane elements of these systems. It is concluded that multiple areas of bioregulators fixation within the limits of the signal cascades are available.
Asunto(s)
Neutrófilos/fisiología , Transducción de Señal/fisiología , 3',5'-AMP Cíclico Fosfodiesterasas/sangre , Adenilil Ciclasas/sangre , Secuencia de Aminoácidos , Animales , Movimiento Celular/fisiología , Datos de Secuencia Molecular , Neutrófilos/citología , Fosfatos de Fosfatidilinositol/sangre , RatasRESUMEN
The authors discuss a possibility of the design of the drug classification on the basis of their interaction with two systems of perception, conduction and realization of external signals by the cell. Review reciprocal interactions between the adenylate cyclase and polyphosphoinositide systems and the polytropic character of the action of biologically active substances within the limits of each system.
Asunto(s)
Preparaciones Farmacéuticas/clasificación , Adenilil Ciclasas/efectos de los fármacos , Adenilil Ciclasas/farmacología , Animales , Interacciones Farmacológicas , Fosfatos de Fosfatidilinositol , Fosfatidilinositoles/farmacología , Receptores de Droga/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The binding of sodium salicylate, sodium mefenamate, ortophen and piroxicam to membranes of erythrocyte ghosts and the effects of the drugs on the membrane microviscosity in carrageenan-induced inflammation were studied by the fluorescent probe method. It was shown that under inflammation the membrane microviscosity decreases and concurrently the affinity of the studied compounds to them increases. Antiphlogistics were found to enhance the membrane viscosity both in control and under inflammation. The possible mechanisms of the described effects of non-steroidal anti-inflammatory agents on biomembranes are discussed.
Asunto(s)
Antiinflamatorios no Esteroideos/metabolismo , Membrana Eritrocítica/metabolismo , Inflamación/metabolismo , Animales , Antiinflamatorios no Esteroideos/farmacología , Membrana Eritrocítica/efectos de los fármacos , Fluidez de la Membrana/efectos de los fármacos , RatasRESUMEN
The binding of nonsteroidal anti-inflammatory drugs (NSAID), voltaren and piroxicam, to the membranes of erythrocyte ghosts and phosphatidylcholine liposomes was studied by the fluorescent probe method. The drugs were shown to possess high affinity to the both types of the membranes. Voltaren was mainly located in the lipid part of erythrocyte ghost membranes, while piroxicam was uniformly distributed between the protein and lipid components of the membranes. The findings suggest that the differences in the binding characteristics of the studied NSAID might determine to a certain extent the specificity of their anti-inflammatory action.
Asunto(s)
Diclofenaco/farmacocinética , Membrana Eritrocítica/metabolismo , Liposomas/farmacocinética , Piroxicam/farmacocinética , Animales , Colorantes Fluorescentes , Técnicas In Vitro , Lípidos de la Membrana/metabolismo , Proteínas de la Membrana/metabolismo , Fosfatidilcolinas/metabolismo , Unión Proteica/efectos de los fármacos , RatasRESUMEN
In experiments on rats it was shown that ethonium pharmacokinetics at intragastric administration may be described within the framework of the two-compartment model with absorption. After administration ethonium cannot be directly absorbed although its absorption proceeds rapidly. The distribution between the central and peripheral compartments is slowed as well as the process of elimination from the blood flow.
Asunto(s)
Antiinfecciosos/metabolismo , Compuestos de Amonio Cuaternario/metabolismo , Absorción , Administración Oral , Animales , Disponibilidad Biológica , Cinética , Masculino , Matemática , Ratas , Factores de TiempoRESUMEN
The paper deals with a regulatory effect of the redox state of nicotinamide coenzymes on glyceroneogenesis in the epididymal fatty tissues involving incorporation of [2-14C] pyruvate into synthetized de novo blood glucose, glycerol and fatty acids of triacyglycerines. Large values of the NAD+/NADH and NADP+/NADPH ratios in cytoplasm and mitochondria promote a high rate of lipogenesis and glucose oxidation processes, which is pronounced in a more intense 14C incorporation into fatty acids than in triacylglycerol glycerols. A decrease in the NAD+/NADH ratio and an increase in the reducing ability of NAD-pairs under fasting intensify glyceroneogenesis in the fatty tissue. The incorporation of [14C] pyruvate into blood glucose in 3.6 times as high, the radioactivity of fatty acids lowers. Nicotinamide administered to animals after fastening inhibits glyceroneogenesis in the fatty tissue, lowering considerably the incorporation of [14C] pyruvate into triacylglycerol glycerol and blood glucose.
Asunto(s)
Tejido Adiposo/metabolismo , Gluconeogénesis , Glicerol/metabolismo , NADP/metabolismo , NAD/metabolismo , Niacinamida/farmacología , Animales , Glucemia/metabolismo , Carbohidratos de la Dieta/administración & dosificación , Epidídimo/metabolismo , Ácidos Grasos/metabolismo , Masculino , Oxidación-Reducción , Piruvatos/metabolismo , Ratas , Triglicéridos/metabolismoRESUMEN
The activity of some NAD- and NADP-dependent dehydrogenases involved in generation of the reducing equivalents for lipogenesis and the activity and some kinetic parameters of ATP-citrate (pro-3S)-lyase from rat liver, i. e. the enzyme involved in the formation of CoASAc, the primary substrate of fatty acid biosynthesis, were studied. The changes in the activity of NADP-dependent dehydrogenase and ATP-citrate(pro-3S)-lyase, as well as the affinity of the latter for sitrate and CoA and the rate of lipogenesis in starved rats and in rats kept on a carbohydrate-rich diet after starvation appeared to be parallel. Nicotinamide decreased the activity of all NADP-dependent dehydrogenases under study, which was especially well-pronounced after nicotinamide addition against increased lipogenesis. The affinity of ATP-citrate(pro-3S)-lyase for citrate and CoA decreased simultaneously with the decrease in the concentration of the latter. These changes can possibly induce the decrease of lipogenesis rate in rat liver after addition of nicotinamide.
Asunto(s)
Lípidos/biosíntesis , Hígado/metabolismo , Niacinamida/farmacología , ATP Citrato (pro-S)-Liasa/metabolismo , Nucleótidos de Adenina/metabolismo , Animales , Carbohidratos de la Dieta/farmacología , Hígado/efectos de los fármacos , Masculino , NADH NADPH Oxidorreductasas/metabolismo , Fosfatos/metabolismo , Ratas , InaniciónRESUMEN
The synthesis of fatty acids and lipids in the rat tissues is inhibited to a considerable extent during fasting and is activated when feeding highly carobhydrate ration to rats after fasting. Nicotinamide (50 mg/100 g of weight) causes a decrease in intensity of 14C incorporation into free fatty acids and lipids of blood, liver, epididimal and perienal fatty tissues. The degree of nicotinamide inhibition of fatty acids and lipids sythesis is in direct dependence on lipogenesis intensity.
Asunto(s)
Acetatos/metabolismo , Ácidos Grasos no Esterificados/biosíntesis , Lípidos/biosíntesis , Niacinamida/farmacología , Tejido Adiposo/metabolismo , Animales , Carbohidratos de la Dieta/administración & dosificación , Ayuno , Hígado/metabolismo , Masculino , RatasRESUMEN
Experimentally-induced alloxan diabetes was characterized in rats by a marked increase in the blood glucose level and by a number of disturbances in the concentration of metabolites and the activity of the enzymes of carbohydrate metabolism in the liver. Stimulation of gluconeogenesis in diabetes was judged by reduction of the redox condition of free NAD- and NADP-couples, by the increase in the concentration of phosphoenolpyruvate, malic oxaloacetate and phosphoenolpyruvate carboxykinase activity of the liver. Nicotinamide in a dose of 50 mg per 100 g of body weight caused a marked reduction in the blood glucose level of diabetic rats. An increase of the [NAD+]/[NADN], [NADP+]/[NADPN] ratio, a reduction of the concentration of phosphoenolpyruvate, malate and phosphoenolpyruvate carboxylase activity pointed to the inhibition of gluconeogenesis and stimulation of glycolysis in the liver of diabetic rats given nicotinamide.