Discovery and characterization of benzyloxy piperidine based dopamine 4 receptor antagonists

Bioorg Med Chem Lett. 2022 Apr 1:61:128615. doi: 10.1016/j.bmcl.2022.128615. Epub 2022 Feb 10.

Abstract

The dopamine receptor 4 (D4R) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the brain, there is mounting evidence pointing to a role for the D4R in the modulation of this network and its subsequent involvement in l-DOPA induced dyskinesias in Parkinson's disease. As part of our continued effort in the discovery of novel D4R antagonists, we report the discovery and characterization of a new 3- or 4-benzyloxypiperidine scaffold as D4R antagonists. We report several D4R selective compounds (>30-fold vs. other dopamine receptor subtypes) with improved in vitro and in vivo stability over previously reported D4R antagonists.

Keywords: Antagonists; Benzyloxypiperidine; D4R; Dopamine 4 receptor; Parkinson’s disease.

Publication types

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

MeSH terms

  • Dopamine Antagonists / chemical synthesis
  • Dopamine Antagonists / chemistry
  • Dopamine Antagonists / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Receptors, Dopamine D4 / antagonists & inhibitors*
  • Receptors, Dopamine D4 / metabolism
  • Structure-Activity Relationship

Substances

  • Dopamine Antagonists
  • Piperidines
  • Receptors, Dopamine D4