The binding of fluorocatecholamines to adrenergic and dopaminergic receptors in rat brain membranes |
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Authors: | Y. Nimit D. Cantacuzene K.L. Kirk C.R. Creveling J.W. Daly |
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Affiliation: | 1. Laboratory of Bioorganic Chemistry, Bethesda, MD 20205, USA;2. Laboratory of Chemistry National Institute of Arthritis, Metabolism and Digestive Diseases National Institutes of Health Bethesda, MD 20205, USA |
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Abstract: | 2-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. |
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