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

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. Boron tribromide 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 analogues. 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 a 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 analogues for the alpha- and beta-adrenergic receptors.

Localization of the mouse α1A-adrenergic receptor (AR) in the brain: α1AAR is expressed in neurons, GABAergic interneurons, and NG2 oligodendrocyte progenitors

“…Experiments were performed at 22 ± 1°C. To minimize oxidation of the selective α‐AR agonist 6FNE (Kirk et al,1979), stock solutions were made fresh and added to oxygenated saline just before their application and high perfusion rates (2–4 cc/min) were maintained. Data were analyzed offline by using Origin (OriginLab Corp., Northampton, MA) and Mini analysis 6.0.1 (Synaptosoft Inc., Decatur, GA).…”

Fluorinated Molecules as Drugs and Imaging Agents in the CNS

“…A classical example of this involves adrenergic receptors. Kirk and coworkers have worked extensively in this field and shown how selectivity can be obtained between alpha and beta receptors depending on location of fluorine on norepinephrine or epinephrine [54][55][56][57]. The metabolic patterns were also affected [56].…”

Structural basis of the selectivity of the β2-adrenergic receptor for fluorinated catecholamines

“…We discovered several years ago that fluorine substitution on the aromatic ring of NE, EPI, and related adrenergic agonists dramatically alters the selectivity of these agonists for α- and β-adrenergic receptors, depending on the site of substitution 4, 5. The 2-fluoro analogues ( 2a,b ) bind selectively to the β 2 –adrenergic receptor while the 6-fluoro analogues ( 3a,b ) bind preferentially to the α 1b –adrenergic receptor.…”