Synthesis and renal vasodilator activity of some dopamine agonist 1-aryl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diols: halogen and methyl analogues of fenoldopam

J Med Chem. 1986 Nov;29(11):2315-25. doi: 10.1021/jm00161a029.

Abstract

Certain 6-halo-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines were found to be potent D-1 dopamine agonists. The 1-(4-hydroxyphenyl) analogues did not have central nervous system activity because their high polarity inhibited entry into the brain. However, these compounds were potent renal vasodilators. Fenoldopam, the 6-chloro analogue, is an especially significant member of the series, and its synthesis, pharmacology, and clinical properties have been studied extensively. The 6-methyl and 6-iodo congeners were potent renal vasodilators, but nonpotent partial D-1 agonists as measured by stimulation of rat caudate adenylate cyclase. A possible rationalization suggests different receptor reserves for these activities. The 9-substituted benzazepines were either inactive or of low potency as dopamine agonists, while the N-methyl analogues had significant antagonist potency as measured by inhibition of dopamine stimulation of rat caudate adenylate cyclase.

MeSH terms

  • Adenylyl Cyclases / analysis
  • Animals
  • Benzazepines / pharmacology*
  • Blood Pressure / drug effects
  • Brain / drug effects
  • Dogs
  • Fenoldopam
  • Receptors, Dopamine / drug effects*
  • Renal Circulation / drug effects*
  • Structure-Activity Relationship
  • Vasodilator Agents / chemical synthesis*
  • Vasodilator Agents / pharmacology

Substances

  • Benzazepines
  • Receptors, Dopamine
  • Vasodilator Agents
  • Adenylyl Cyclases
  • Fenoldopam