RESUMEN
The atypical profile of 2-phenyl-4[2-(4-piperidinyl) ethyl]quinoline (PK 8165), a quinoline derivative with pure anticonflict properties, seems to be due to the fact that this compound is a partial agonist of benzodiazepine receptors. The drug PK 8165 is a competitive inhibitor of benzodiazepine binding sites with a Hill coefficient near unity. Opposite to 3-methyl-6-(3-trifluoromethylphenyl)2,4-triazolo(4,5-b)pyridazine (CL 218,872) it was unable to discriminate between BZ1 and BZ2 receptors in sections of brain. However, modulation by gamma-aminobutyric acid (GABA) and the effect of photolabelling by flunitrazepam on the affinity of PK 8165 indicated that GABA or photolabelling shifts of PK 8165 were between full agonists and antagonists. By itself PK 8165 was unable to modify the levels of cGMP in the cerebellum, but potentiated the lowering of levels of cGMP by diazepam and did not present antagonistic properties of this effect.
Asunto(s)
Encéfalo/efectos de los fármacos , Conflicto Psicológico , Quinolinas/metabolismo , Receptores de GABA-A/efectos de los fármacos , Animales , Encéfalo/metabolismo , GMP Cíclico/metabolismo , Flunitrazepam/metabolismo , Masculino , Ratas , Receptores de GABA-A/metabolismo , Estimulación Química , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
The [3H]PK 11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinolinecarboxamide, binding sites in rat cardiac membranes are saturable, with high affinity, specific GABA-independent and correspond to the peripheral type of benzodiazepine. The order of potency of displacing agents was: PK 11195 greater than RO5-4864 greater than dipyridamole greater than diazepam greater than clonazepam. The Bmax obtained with [3H]PK 11195 was equivalent of the Bmax obtained with [3H]RO5-4864 in the same experimental conditions. However thermodynamic analysis indicates that the [3H]PK 11195 binding was entropy driven whereas the [3H]RO5-4864 binding was enthalpy driven. Consequently PK 11195 might be an antagonist of these binding sites and RO5-4864 an agonist or a partial agonist. The simultaneous use of both drugs might help to elucidate the physiological relevance of peripheral benzodiazepine binding sites.
Asunto(s)
Benzodiazepinonas/metabolismo , Isoquinolinas/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Clonazepam/metabolismo , Diazepam/metabolismo , Dipiridamol/metabolismo , Ligandos , Masculino , Membranas/metabolismo , Miocardio/metabolismo , Ratas , Receptores de GABA-A , TermodinámicaRESUMEN
A subacute treatment, 500 mg/kg I.P. twice daily during 5 days, by L-methionine provoked an increase in the Bmax of [3H]-spiperone binding in the striatum of the rat. This increase was associated to a decrease in membrane microviscosity. However in these conditions no changes were found in the [3H]-DHA, [3H]QNB bindings or in the brain dopamine sensitive adenylate cyclase activity. L-methionine treatment reduced the accumulation of Dopa after NSD 1015 and antagonized the decrease in striatal acetylcholine provoked by haloperidol. Thus L-methionine might be a new potential drug for Parkinson's disease treatment.
Asunto(s)
Cuerpo Estriado/metabolismo , Metionina/farmacología , Receptores Dopaminérgicos/efectos de los fármacos , Animales , Cuerpo Estriado/efectos de los fármacos , Masculino , Fluidez de la Membrana/efectos de los fármacos , Ratas , Ratas EndogámicasRESUMEN
[3H] RO5-4864 binding sites have been characterized in kidney, heart, brain, adrenals and platelets in the rat. In all these organs the following order of potency in the RO5-4864 displacement was found: RO5-4864 greater than diazepam greater than clonazepam indicating that they correspond to the "peripheral type" of benzodiazepine binding sites. PK 11195, an isoquinoline carboxamide derivative, displaces [3H] RO5-4864 from its binding sites in all the organs. PK 11195 was as potent as RO5-4864 in the platelets, heart, adrenals, kidney and several brain regions (midbrain, hypothalamus, medulla + pons and hippocampus. However it was 5 to 10 times more effective in cortex and striatum. In conclusion PK 11195 might represent a new tool to elucidate the physiological relevance of "peripheral type" benzodiazepine binding sites and might help to discriminate the hypothetical subclasses of these binding sites.
Asunto(s)
Benzodiazepinonas/metabolismo , Isoquinolinas/metabolismo , Receptores de Superficie Celular/metabolismo , Glándulas Suprarrenales/metabolismo , Animales , Plaquetas/metabolismo , Encéfalo/metabolismo , Clonazepam/metabolismo , Diazepam/metabolismo , Técnicas In Vitro , Riñón/metabolismo , Masculino , Miocardio/metabolismo , Ratas , Ratas Endogámicas , Receptores de GABA-A , Distribución TisularRESUMEN
[3H]spiroperidol binding to lymphocytes was measured in untreated paranoid or disorganized and treated paranoid schizophrenic patients. An increase in the Bmax was detected in untreated paranoid patients but a decrease was found in the disorganized patients. No difference was detected in the KD value. Neuroleptic treatment produced a decrease in the Bmax without affecting the KD value. Such results did not comply with the down regulation but might be explained by a change in membrane viscosity as [3H]spiroperidol binding sites on lymphocytes were coupled to phospholipid methylation.
Asunto(s)
Butirofenonas/metabolismo , Linfocitos/metabolismo , Esquizofrenia/metabolismo , Espiperona/metabolismo , Adulto , Factores de Edad , Antipsicóticos/farmacología , Femenino , Humanos , Masculino , Receptores de Droga/efectos de los fármacos , Factores SexualesRESUMEN
The specific binding of the dopamine antagonist spiroperidol was studied in leukemic cell samples of various phenotypes. Among these only B-cell samples from chronic lymphocytic leukemias (7/7) and some "null" cell samples from acute lymphoblastic leukemias (2/7) showed specific binding. B cells from a prolymphocytic leukemia were negative as were also T-lymphoïd and non-lymphoïd leukemic cells at different stages of maturation. This pattern can be clearly correlated with the previous results obtained with normal blood cells and on cell lines. Moreover, it suggests that the detection of spiroperidol binding sites could provide a new means of distinguishing different phenotypes among B cells and early lymphoïd cells. Our results open the way to further studies which might show a correlation between spiroperidol binding sites and the new immunological markers defining subsets among non-T lymphoïd cells, as well as defining their physiological meaning.
Asunto(s)
Butirofenonas/metabolismo , Leucemia/metabolismo , Receptores Dopaminérgicos/metabolismo , Espiperona/metabolismo , Humanos , Cinética , Leucemia/inmunología , Leucemia Linfoide/metabolismo , Fenotipo , Formación de RosetaRESUMEN
Eleven patients with previously untreated Parkinson's disease were treated with L-Methionine for periods from 2 weeks to 6 months. The treatment was well supported and good improvement in clinical signs, particularly akinesia and rigidity, appeared within approximately three weeks, the effect on tremor being less marked. Therapeutic effects were similar to those observed with L-dopa treatment. Correlation of clinical effects with a marked increase in the number of 3H-Spiroperidol binding sites (Bmax) to lymphocytes was noted. This therapeutic effect suggests the role played by modifications of membrane fluidity on dopaminergic receptors, both lymphocytic and striatal, in the etiology of Parkinson's disease, and opens up new therapeutic possibilities in this disease.
Asunto(s)
Metionina/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Femenino , Humanos , Masculino , Metionina/metabolismo , Enfermedad de Parkinson/metabolismo , Receptores Dopaminérgicos/metabolismoRESUMEN
Normal rabbit bone marrow erythroid cells have been found to possess insulin receptors. Their number shows an inverse relationship with the stage of differentiation, ranging from 20,000 sites/cell in the less mature to 8,000 sites/cell in the more mature cells. In addition, insulin rapidly stimulates the incorporation of leucine into protein in these cells and in rabbit, human, and rat peripheral blood reticulocytes. In rat reticulocytes, the concentration range of the hormone required for this phenomenon is from 25 to 625 microU/ml.