Identification of a 2-phenyl-substituted octahydrobenzo[f]quinoline as a dopamine D₃ receptor-selective full agonist ligand

Bioorg Med Chem. 2012 Nov 1;20(21):6366-74. doi: 10.1016/j.bmc.2012.08.058. Epub 2012 Sep 8.

Abstract

This work describes the identification of a novel class of octahydrobenzo[f]quinolines as dopamine D(3)-selective full agonists. We developed a facile method that utilizes Suzuki coupling for easy incorporations of various substituted pendant rings into the scaffold. A small focused library of octahydrobenzo[f]quinolines 5 was synthesized, and these compounds demonstrated at least 14-fold D(2)-like selectivity over D(1) in native porcine striatal tissue. Furthermore, n-propyl analog 5f was found to be a high affinity (K(i)=1.1 nM) D(3) dopamine full agonist with 145-fold selectivity over the D(2) receptor and about 840-fold selectivity over the D(1) receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Quinolines / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Receptors, Dopamine D3 / agonists*
  • Receptors, Dopamine D3 / metabolism
  • Structure-Activity Relationship

Substances

  • Ligands
  • Quinolines
  • Receptors, Dopamine D3
  • octahydrobenzo(f)quinoline