Assessment of dopamine D₁ receptor affinity and efficacy of three tetracyclic conformationally-restricted analogs of SKF38393

Bioorg Med Chem. 2011 Sep 15;19(18):5420-31. doi: 10.1016/j.bmc.2011.07.057. Epub 2011 Aug 3.

Abstract

To assess the effect of conformational mobility on receptor activity, the β-phenyl substituent of dopamine D(1) agonist ligands of the phenylbenzazepine class, (±)-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepine-11,12-diol (8), and its oxygen and sulfur bioisosteres 9 and 10, respectively, were synthesized as conformationally-restricted analogs of SKF38393, a dopamine D(1)-selective partial agonist. Compounds trans-8b, 9, and 10 showed binding affinity comparable to that of SKF38393, but functionally, they displayed only very weak agonist activity. These results suggest that the conformationally-restricted structure of the analogs cannot adopt a binding orientation that is necessary for agonist activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / chemical synthesis
  • 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 / pharmacology*
  • Binding, Competitive / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Receptors, Dopamine D1 / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Receptors, Dopamine D1
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine