Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior

Bioorg Med Chem. 2017 Jul 1;25(13):3491-3499. doi: 10.1016/j.bmc.2017.04.036. Epub 2017 Apr 29.

Abstract

Dopamine D3 receptor-mediated networks have been associated with a wide range of neuropsychiatric diseases, drug addiction and food maintained behavior, which makes D3 a highly promising biological target. The previously described dopamine D3 receptor ligand FAUC 329 (1) showed protective effects against dopamine depletion in a MPTP mouse model of Parkinson's disease. We used the radioligand [18F]2, a [18F]fluoroethoxy substituted analog of the lead compound 1 as a molecular tool for visualization of D3-rich brain regions including the islands of Calleja. Furthermore, structural modifications are reported leading to the pyrimidylpiperazine derivatives 3 and 9 displaying superior subtype selectivity and preference over serotonergic receptors. Evaluation of the lead compound 1 on cocaine-seeking behavior in non-human primates showed a substantial reduction in cocaine self-administration behavior and food intake.

Keywords: Autoradiography; Dopamine D(3) receptor; Drug maintained behavior; Fluorine-18; Food maintained behavior; Positron emission tomography (PET); Selective D(3) antagonist; Self-administration; Subtype selectivity.

Publication types

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

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Mice
  • Molecular Structure
  • Positron-Emission Tomography
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Rats
  • Receptors, Dopamine D3 / antagonists & inhibitors*
  • Receptors, Dopamine D3 / metabolism
  • Structure-Activity Relationship

Substances

  • 2-(4-(4-chlorophenyl)piperazin-1-ylmethyl)pyrazolo(1,5-a)-pyridine
  • Ligands
  • Pyrazoles
  • Pyridines
  • Receptors, Dopamine D3