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
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 paper embraces information about the character of interaction between pharmacologically active ligands and 11 G-protein-dependent receptors of neurotransmitters. The data are analyzed by the methods of correlation and cluster analyses and of main components. An essential pharmacological affinity is revealed to exist between the receptors which regulate an inhibitory link of the adenylate cyclase system and receptors which activate Ca(2+)-mobilizing polyphosphoinositide system of secondary transmitters. Receptors which activate adenylate cyclase are rather different pharmacologically from two previous groups. Interrelation between the structure and physico-chemical properties of binding sites on receptors and efficiency of their interaction with ligand is discussed.
Asunto(s)
Receptores de Amina Biogénica/metabolismo , Adenilil Ciclasas/metabolismo , Interpretación Estadística de Datos , Activación Enzimática , Proteínas de Unión al GTP/fisiología , Ligandos , Matemática , Receptores de Amina Biogénica/efectos de los fármacosRESUMEN
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.