Discovery, optimization, and characterization of novel D2 dopamine receptor selective antagonists

J Med Chem. 2014 Apr 24;57(8):3450-63. doi: 10.1021/jm500126s. Epub 2014 Apr 10.


The D2 dopamine receptor (D2 DAR) is one of the most validated drug targets for neuropsychiatric and endocrine disorders. However, clinically approved drugs targeting D2 DAR display poor selectivity between the D2 and other receptors, especially the D3 DAR. This lack of selectivity may lead to undesirable side effects. Here we describe the chemical and pharmacological characterization of a novel D2 DAR antagonist series with excellent D2 versus D1, D3, D4, and D5 receptor selectivity. The final probe 65 was obtained through a quantitative high-throughput screening campaign, followed by medicinal chemistry optimization, to yield a selective molecule with good in vitro physical properties, metabolic stability, and in vivo pharmacokinetics. The optimized molecule may be a useful in vivo probe for studying D2 DAR signal modulation and could also serve as a lead compound for the development of D2 DAR-selective druglike molecules for the treatment of multiple neuropsychiatric and endocrine disorders.

Publication types

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

MeSH terms

  • Dopamine Antagonists / chemical synthesis*
  • Dopamine Antagonists / pharmacology
  • Dopamine D2 Receptor Antagonists*
  • Drug Discovery
  • HEK293 Cells
  • High-Throughput Screening Assays
  • Humans
  • Structure-Activity Relationship


  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists