Syntheses of 2,5- And 2,6-difluoronorepinephrine, 2,5-difluoroepinephrine, and 2,6-difluorophenylephrine: Effect of Disubstitution With Fluorine on Adrenergic Activity

J Med Chem. 1993 Nov 26;36(24):3947-55. doi: 10.1021/jm00076a024.

Abstract

Synthetic routes to difluorinated analogs of the adrenergic agonists, norepinephrine (NE), epinephrine (E), and phenylephrine (PE) have been developed. The syntheses were based on elaboration of the ethanolamine side chains from the appropriately polyfunctionalized benzaldehydes. The benzaldehydes were prepared from precursor difluorinated benzenes by sequential regioselective lithiations and reaction with electrophiles to introduce hydroxyl and carboxaldehyde functionalities. Binding and functional assay data demonstrate that the 2,6-difluorinated analogs are relatively inactive at both alpha- and beta-adrenergic receptors. These results are consistent with earlier observations that 2-fluoro substitution of adrenergic agonists decreases alpha-adrenergic activity whereas 6-fluoro substitution decreases beta-adrenergic activity.

MeSH terms

  • Animals
  • Cell Membrane / metabolism
  • Cerebral Cortex / metabolism
  • Dioxanes / metabolism
  • Epinephrine / analogs & derivatives*
  • Epinephrine / chemistry
  • Epinephrine / pharmacology
  • Fluorine Compounds / chemical synthesis*
  • Fluorine Compounds / pharmacology
  • Guinea Pigs
  • Inositol Phosphates / metabolism
  • Norepinephrine / analogs & derivatives*
  • Norepinephrine / chemistry
  • Norepinephrine / pharmacology
  • Phenylephrine / analogs & derivatives*
  • Phenylephrine / chemistry
  • Phenylephrine / pharmacology
  • Prazosin / metabolism
  • Rats
  • Receptors, Adrenergic, alpha / drug effects
  • Receptors, Adrenergic, alpha / metabolism
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta / metabolism
  • Structure-Activity Relationship
  • Synaptosomes / metabolism

Substances

  • Dioxanes
  • Fluorine Compounds
  • Inositol Phosphates
  • Receptors, Adrenergic, alpha
  • Receptors, Adrenergic, beta
  • Phenylephrine
  • (2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane
  • Norepinephrine
  • Prazosin
  • Epinephrine