3H-clozapine binding to rat brain membranes
Abstract
3H-Clozapine binds specifically and with high affinity (KD = 1.3 nM) to rat brain membranes. About two thirds of reversibly bound 3H-clozapine are displaced by hyoscyamine in a stereospecific manner, suggesting interaction of clozapine with muscarinic cholinergic receptors. Most of the remaining 3H-clozapine binding is stereospecifically inhibited by butaclamol, but this binding component seems not to be related to dopamine receptors.
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Cited by (16)
Dopamine receptors in the central nervous system
1982, International Review of NeurobiologyDopamine (DA) is an important central nervous system (CNS) pituitary modulator of prolactin, β-endorphin, and α-MSH secretion. This chapter discusses central DA receptors, the pharmacological characteristics and anatomical localizations of the several distinct DA-receptor subtypes delineated through radioligand binding and biochemical studies, the functions of these receptors, and actions of dopaminergic agonists and antagonists. Although, several DA receptors are thought to function in the CNS, there is a great deal yet to be understood regarding their biochemical, physiological, and behavioral roles. Radioligand-binding studies have proved to be very useful in determining the mechanisms involved in the regulation and alteration of neuronal activity; however, future investigations may exploit this technique for the study of neuronal and neurochemical plasticity. Regulation of neurotransmitter and hormone-receptor binding should be examined during the aging process, because if receptor regulation is progressively disturbed, it may be amenable to pharmacological therapy.
Quantitative assessment of heterogeneous <sup>3</sup>H-spiperone binding to rat neostriatum and frontal cortex
1980, Life SciencesAnomalies of the binding of 3Hspiperone to rat cerebral membranes have been examined. By employing a very low ligand concentration () we have demonstrated that even within the corpus striatum, 3Hspiperone appears to bind to multiple sites and that dopaminergic and serotonergic agents can selectively inhibit from these sites. In the corpus striatum, 75–80% of the 3Hspiperone specific binding can be inhibited with high affinity by dopaminergic drugs while some 20–30% is inhibited with high affinity by serotonergic compounds. The two 3Hspiperone sites, which we have shown to have affinities of 31 and 325 pM, may therefore represent dopaminergic and serotonergic sites. At higher concentrations of 3Hspiperone, however, the picture may be complicated by a further low affinity site. The great selectivity shown by dopaminergic agonists for the two 3Hspiperone sites explains the ‘flattened’ displacement curves reported for 3Hspiperone/agonist interactions. As dopaminergic agents show the greater affinity for the high affinity 3Hspiperone site, it is tempting to speculate that this site has the greatest association with the dopamine receptor.
The binding of fluorocatecholamines to adrenergic and dopaminergic receptors in rat brain membranes
1980, Life Sciences2-Fluoronorepinephrine (IC50 ≈0.7 μM) is a relatively selective ligand for displacement of radioactive dihydroalprenolol from β1-adrenergic receptors in membrane preparations from rat cerebral cortex. It is less potent (IC50 ≈10 μM) in displacing dihydroalprenolol from β2-adrenergic receptors in rat cerebellar membranes and in displacing clonidine from α2-adrenergic receptors in rat cerebral cortical membranes. It is much less potent (IC50 > 100 μM) in displacing WB-4101 from α1-adrenergic receptors in rat cerebral cortical membranes. In contrast, 6-fluoronorepinephrine is relatively selective for α-adrenergic receptors, being at least 50–200 times more potent at such receptors than at β-adrenergic receptors. 5-Fluoronorepinephrine like norepinephrine does not exhibit remarkable selectivity towards α- and β-adrenergic receptors. The 2-, 5- and 6-fluorodopamines are more potent ligands at α1-adrenergic receptors than at α2- and β-adrenergic receptors but the specificity is not markedly affected by the position of the fluorine substituent. The results suggest that the specificity exhibited by the 2- and 6-fluoronorepinephrine at adrenergic receptors is not primarily due to fluorine-induced changes in the physicochemical properties of the aromatic ring, but instead to stereoselective interactions of the ethanolamine side chain of norepinephrine with fluorine at either the 2- or 6-ring positron. The fluorodopamines like dopamine itself are more potent at dopaminergic than at α- or β-adrenergic receptors. The 2-, 5- and 6-fluorodopamines are all nearly equipotent with dopamine in the displacement of radioactive spiroperidol from dopaminergic receptors in membrane preparations from rat striatum, while the 2- and 6-fluorodopamine are somewhat less potent than dopamine or 5-fluorodopamine in displacement of radioactive apomorphine in striatal membranes.
Loss of β-adrenoceptor binding sites in rat striatum following kainic acid lesions
1979, European Journal of PharmacologyIntrastriatal injection of kainic acid (5 nmoles) to rats led to a severe destruction of nerve cell bodies through-out the caudate-putamen complex and an extensive proliferation of glial cells. Lesioned striata displayed a significatn 23% loss of β-adrenoceptor binding sites 21–24 days after injection of kainic acid. Further analysis of these changes revealed that his loss of sites was selectively within the β1 receptor population. Although these results do not rule out a partial glial cell localisation for β-adrenoceptors, they do indicate that at least a proportion of β1 receptors are present on striatal perikarya
Abnormal locomotion in rats after bilateral intrastriatal injection of kainic acid
1979, Life SciencesThe locomotion changes, after bilateral injection of kainic acid into the striata, are characterized by increased swing time and decreased stance time. This may be analogous to the locomotion pattern in patients with Huntington's Disease.
Multiple dopamine receptors and behavior
1983, Neuroscience and Biobehavioral ReviewsThe therapeutic effects of dopamine (DA) agonists and DA antagonists used in the treatment of schizophrenia (antipsychotics, DA antagonists), Huntington's chorea (DA antagonists) and Parkinson's disease (antiparkinsonian agents, DA agonists) have been thought to result largely from actions on DA receptors located in the striatum (caudate nucleus and putamen). Many of the classical drugs used to treat these disorders are known to have a high incidence of extrapyramidal side effects (EPS). However, a number of drugs, the atypical antipsychotics and antiparkinsonian agents, have been developed which have a low incidence of EPS. It has been of enormous interest to researchers and clinicians alike to determine what characteristics of the atypical antipsychotics and antiparkinsonian agents are responsible for their unique behavioral profile. Because all of the antipsychotics and antiparkinsonian agents act on DA receptors, much attention has focused on potential differences in the interactions of the atypical agents with DA receptors. An hypothesis that has been raised, due to the knowledge that there are multiple subtypes of DA receptors located in the striatum, is that the atypical agents could have their therapeutic actions as a result of an interaction with one specific subtype of DA receptor. This review emphasizes two major points: (1) it is unlikely that the atypical antipsychotics and antiparkinsonian agents interact with only one subtype of DA receptor, or have their therapeutic actions only through that receptor; (2) other pharmacological characteristics of these agents are more critically involved in their unique behavioral effects. The applicability of animal models to assess the pharmacological and behavioral profiles of these agents is discussed, and the relevance to the clinical profiles of these agents is emphasized.