High Affinity For Dopamine Receptors Research Articles

Síndrome neuroléptico maligno inducido por risperidona y facilitado por sepsis de origen urinario: clínica y fisiopatología.

La risperidona es un antagonista selectivo monoaminérgico, con una elevada afinidad por receptores dopaminérgicos, que puede producir síndrome neuroléptico maligno (SNM), considerado una emergencia médica con alto riesgo de muerte. Tiene una incidencia de hasta el 3% y su mortalidad está entre el 10 y 20%. Se reporta el caso de una paciente de 56 años, que reunía los criterios clínicos del SNM, inducido por el uso de risperidona y facilitado por una sepsis de origen urinario. El tratamiento se condujo con un agente agonista dopaminérgico y cambio del antipsicótico, procedimientos que resultaron en una adecuada evolución clínica. El SNM es una entidad de baja prevalencia, para la cual existen criterios diagnósticos con especificidad y sensibilidad mayor del 90%, por lo que debe diferenciarse claramente de otras patologías. Se discute el mecanismo mediante el cual la infección urinaria facilitaría la ocurrencia de esta enfermedad. El diagnóstico precoz mejora la respuesta al manejo adecuado que se establezca en cada caso.

Investigation of possible association between Ser9Gly polymorphism of the D3 dopaminergic receptor gene and response to typical antipsychotics in patients with schizophrenia

Typical antipsychotics have a high affinity for dopamine receptors. It is therefore of interest to investigate such loci in pharmacogenetic studies on psychosis. We investigated the hypothesis that Ser9Gly polymorphism of the DRD3 gene may play a role in the differences in individual response to typical antipsychotics between schizophrenic patients. The sample was composed of 53 good responders and 59 poor ones. No significant differences between the good and poor responders were found in the allelic distribution (good responders: Ser9 61.32%, Gly9 38.67%; poor responders: Ser9 64.40%, Gly9 35.59%; odds ratio, OR = 0.88, 0.49 < OR < 1.56; chi2 = 0.23, 1 degree of freedom, df, p = 0.63) and genotype distribution (good responders: Ser9/Ser9 37.73%, Ser9/Gly9 47.16%, Gly9/Gly9 15.09%; poor responders: Ser9/Ser9 42.37%, Ser9/Gly9 44.06%, Gly9/Gly9 13.55%; chi2 = 0.25, 2 df, p = 0.88). Nor was there any association with homozygosity (good responders: homozygous: 52.82%, heterozygous: 47.16%; poor responders: homozygous: 55.92%, heterozygous: 44.06%; odds ratio, OR = 0.88, 0.39 < OR < 1.99; chi2 = 0.11, 1 df, p = 0.74). The results did not support the hypothesis that Ser9Gly polymorphism of the DRD3 gene influences the response to typical antipsychotics in our sample of schizophrenics.

Brain distribution of selected antipsychotics in schizophrenia

The brain distribution of phenothiazine antipsychotics in 22 confirmed schizophrenic and 11 control subjects were collected at autopsy. Specimens were homogenized, extracted with n-butyl chloride, and analyzed via liquid chromatography–mass spectrometry, using atmospheric pressure electrospray ionization operating in the positive mode. Drug concentrations normalized for those observed in cerebellum showed three distinct patterns of distribution corresponding to different structural features of each type of phenothiazine. Those drugs with high affinity for dopamine receptors were detected in the highest concentrations in regions with high concentrations of such receptors. However, those associated with relatively lower dopaminergic activity were found in the highest concentration in the occipital cortex, a region with a relatively low concentration of dopamine receptors. The regional brain distribution of thioridazine and its metabolites was concentration dependent. These results have implications for determining the role of these drugs in the sudden and unexpected deaths of schizophrenics.

Radioiodinated 2′-iodospiperone: A new radioligand for in vivo dopamine receptor study

In vivo dopamine receptor binding of the newly synthesized ligand, 125I-2′-iodospiperone ( 125I-2′-ISP), was studied in mouse brain. The highest accumulation was found in the striatum. Analysis of the striatal homogenate showed the 125I-2′-ISP to be metabolically stable. Furthermore, this striatal binding was saturable and displaced only by dopaminergic drugs. On the other hand, the accumulation in the cortex was as low as that of the cerebellum and uneffected by the administration of serotoninergic drugs and dopaminergic drugs; results assessed by macroautoradiographic studies. Thus, the newly synthesized 125I-2′-ISP presented high affinity for dopamine receptors in vivo and therefore, holds great potential for the in vivo dopamine receptor studies, provided 123I becomes readily available.

In vitro evaluation of radioiodinated butyrophenones as radiotracer for dopamine receptor study

Radioiodinated butyrophenone compounds are attracting the interest of those working on dopamine receptor studies; structure-activity relationship study has revealed the ortho position of the p-fluorobutyrophenone moiety as a very plausible iodination site. Various synthesized butyrophenones iodinated at the ortho position of p-fluorobutyrophenone moiety, 2′- iodohaloperidol (2′-IHP), 2′-iodotrifluperidol (2′-ITP) and 2′-iodospiperone (2′-ISP) were tested for their abilities to inhibit 3H-spiperone (SP) binding for the dopamine (D-2) receptor, together with reference compounds (SP, haloperidol (HP) and 4-iodospiperone (4- ISP)). The order of binding affinity of the tested compounds was SP > 2′-ISP > HP > 4-ISP > 2′-IHP > 2′- ITP. Whereas, the serotonin (S-2) receptor binding affinity of SP and its iodinated analogues were in the order of SP > > 4-ISP > 2′-ISP. Furthermore, in the saturation binding study using the striatal membrane preparations, the 2′-ISP displayed a K D of 0.25 nM with maximum number of binding site B max of 210 fmol/mg protein. These data indicated the 2′-ISP as holding high affinity for dopamine receptors and a low affinity for serotonin receptors. Thus, the 125I-2′-ISP was a very potent radioligand for in vitro dopamine (D-2) receptor studies, and 123I-2′-ISP holds very promising characteristics as for in vivo dopamine receptor studies, as well.

Effects of iminodibenzyl antipsychotic drugs on cerebral dopamine and α-adrenergic receptors

The iminodibenzyl antipsychotic drugs, clocapramine, carpipramine and Y-516 were studied in order to elucidate their mechanisms of action. They all accelerated the accumulation of the dopamine (DA) metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC), in the striatum and nucleus accumbens of the rat brain. Only Y-516 antagonized in vivo the apomorphine-induced inhibition of DA synthesis as estimated from the accumulation of 3,4-dihydroxyphenylalanine (DOPA) in the decarboxylase-inhibited rat striatum after cessation of nerve impulse flow. All three drugs showed high affinity for DA receptors labelled by [ 3H]haloperidol and [ 3H]ADTN in the rat striatum in vitro, with the order of potency Y-516 > clocapramine > carpipramine. All accelerated the accumulation of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), in mouse brain. They showed high affinity for α 1-adrenoceptors labelled by [ 3H]WH 4101 and for α 2-adrenoceptors labelled by [ 3H] clonidine in the rat cerebral cortex in vitro. Although they all had the same level of affinity for the α 1-adrenoceptors, Y-516 had less affinity for the α 2-adrenoceptors than did clocapramine and carpipramine. The above results indicate that these drugs are potent DA antagonists which block α 1- and α 2-adrenoceptors in the brain.

The pharmacology of sulpiride—A dopamine receptor antagonist

1. 1. The clinical and experimental pharmacology of sulpiride, its effects on the CNS, gastrointestinal tract and cardiovascular system have been reviewed. 2. 2. The majority of its actions are attributable to blockade of dopamine receptors. 3. 3. Although sulpiride has a high affinity for dopamine receptors involved in emesis and prolactin secretion, it lacks part of the behavioural and biochemical profiles of the classical dopamine receptor antagonist neuroleptics. 4. 4. In the cardiovascular system, sulpiride is a potent prejunctional dopamine receptor antagonist but has variable effectiveness in postjunctional dopamine receptor models. 5. 5. These properties are discussed with reference to the mechanisms of action of sulpiride and the classification of dopamine receptors.