Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D4R) antagonists

Bioorg Med Chem Lett. 2016 May 15;26(10):2481-2488. doi: 10.1016/j.bmcl.2016.03.102. Epub 2016 Mar 30.

Abstract

Herein, we report the synthesis and structure-activity relationship of a series of chiral alkoxymethyl morpholine analogs. Our efforts have culminated in the identification of (S)-2-(((6-chloropyridin-2-yl)oxy)methyl)-4-((6-fluoro-1H-indol-3-yl)methyl)morpholine as a novel potent and selective dopamine D4 receptor antagonist with selectivity against the other dopamine receptors tested (<10% inhibition at 1μM against D1, D2L, D2S, D3, and D5).

Keywords: Antagonist; Dopamine 4 receptor; Dopamine Selectivity; L-DOPA-induced dyskinesia; Morpholine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dopamine Antagonists / chemical synthesis
  • Dopamine Antagonists / chemistry*
  • Dopamine Antagonists / pharmacology*
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Microsomes, Liver / drug effects
  • Morpholines / chemistry*
  • Rats
  • Receptors, Dopamine D4 / antagonists & inhibitors*
  • Structure-Activity Relationship*

Substances

  • Dopamine Antagonists
  • Morpholines
  • Receptors, Dopamine D4