Synthesis and biological properties of 2-, 5-, and 6-fluoronorepinephrines

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Abstract
2-Fluoro-, 5-fluoro- and 6-fluorodimethoxybenzaldehydes were prepared by photochemical decomposition of the corresponding diazonium fluoroborates. The aldehydes were converted to the cyanohydrin trimethylsilyl ethers, which, in turn, were reduced to the dimethoxyphenethanolamines. BBr3 demethylation afforded the racemic ring-fluorinated norepinephrines. An alternate route, using the dibenzyloxyfluoroaldehyde, was also used to prepare 6-fluoronorepinephrine. The fluorine substituent markedly increases the phenolic acidities of these analogs. The biological properties conferred upon norepinephrine by the fluorine substituents in peripheral and central adrenergically responsive systems clearly demonstrate that 2-fluoronorepinephrine is a nearly pure .beta.-adrenergic agonist, while 6-fluoronorepinephrine is an .alpha.-adrenergic agonist. 5-Fluoronorepinephrine retains both .beta.- and .alpha.-adrenergic agonist properties. Receptor-binding studies with specific radiolabeled ligands indicate that the specificity conferred by the site of fluorine substituents results from a change in the affinity of these analogs for the .alpha.- and .beta.-adrenergic receptors. Tests were done on guinea pig atria, aortic strip and ileum, and on rat cerebral cortical slice.

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