Receptor affinities of dopamine D1 receptor-selective novel phenylbenzazepines

Eur J Pharmacol. 2003 Aug 8;474(2-3):137-40. doi: 10.1016/s0014-2999(03)02008-9.

Abstract

We prepared a series of 18 novel substituted phenylbenzazepine congeners of the dopamine D1/D5 receptor partial-agonist SKF-83959 (R,S-3-methyl-6-chloro-7,8-dihydroxy-1-[3'-methylphenyl]-2,3,4,5-tetrahydro-1H-benzazepine) and characterized their potency and selectivity in assays of dopamine, 5-HT and adrenoceptors in rat brain tissue or membranes of genetically transfected cells. The R-enantiomer of SKF-83959 (MCL-202) and three other novel racemic 1-phenyl-7,8-dihydroxybenzazepines (MCL-204, -203, and -207) showed very high dopamine D5 receptor affinity; MCL-209 displayed the greatest dopamine D5 receptor affinity. These five potent novel ligands also had >100-fold selectivity for dopamine D1 over dopamine D2, D3, serotonin 5-HT-2A receptors and alpha2-adrenoceptors. They require further functional testing to characterize their intrinsic activity, and for potential stimulant-antagonist actions, as observed with SKF-83959 and MCL-202.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / analogs & derivatives*
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / chemistry
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / metabolism
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
  • Animals
  • Benzazepines / chemistry*
  • Benzazepines / metabolism*
  • Benzazepines / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • CHO Cells
  • Cricetinae
  • Humans
  • Male
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / agonists*
  • Receptors, Dopamine D1 / metabolism*
  • Structure-Activity Relationship

Substances

  • Benzazepines
  • Receptors, Dopamine D1
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
  • SK&F 83959