Design, synthesis, and evaluation of potent and selective ligands for the dopamine 3 (D3) receptor with a novel in vivo behavioral profile

J Med Chem. 2008 Oct 9;51(19):5905-8. doi: 10.1021/jm800471h. Epub 2008 Sep 12.

Abstract

A series of compounds structurally related to pramipexole were designed, synthesized, and evaluated as ligands for the dopamine 3 (D3) receptor. Compound 12 has a K(i) value of 0.41 nM to D3 and a selectivity of >30000- and 800-fold over the D1-like and D2 receptors, respectively. Our in vivo functional assays showed that this compound is a partial agonist at the D3 receptor with no detectable activity at the D2 receptor.

Publication types

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

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Benzothiazoles / chemical synthesis*
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacology*
  • Binding Sites / drug effects
  • Binding, Competitive / drug effects
  • Dopamine Agonists / chemical synthesis*
  • Dopamine Agonists / chemistry
  • Dopamine Agonists / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Hydrogen Bonding
  • Hypothermia / chemically induced
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Pramipexole
  • Rats
  • Receptors, Dopamine D1 / agonists
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D3 / agonists*
  • Sensitivity and Specificity
  • Solubility
  • Stereoisomerism
  • Structure-Activity Relationship
  • Yawning / drug effects

Substances

  • Benzothiazoles
  • Dopamine Agonists
  • Ligands
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Pramipexole