Highly Selective Dopamine D 3 Receptor Antagonists with Arylated Diazaspiro Alkane Cores

J Med Chem. 2017 Dec 14;60(23):9905-9910. doi: 10.1021/acs.jmedchem.7b01248. Epub 2017 Nov 21.

Abstract

A series of potent and selective D3 receptor (D3R) analogues with diazaspiro alkane cores were synthesized. Radioligand binding of compounds 11, 14, 15a, and 15c revealed favorable D3R affinity (Ki = 12-25.6 nM) and were highly selective for D3R vs D3R (ranging from 264- to 905-fold). Variation of these novel ligand architectures can be achieved using our previously reported 10-20 min benchtop C-N cross-coupling methodology, affording a broad range of arylated diazaspiro precursors.

Publication types

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

MeSH terms

  • Alkanes / chemistry
  • Alkanes / pharmacology
  • Animals
  • Cell Line
  • Dopamine Antagonists / chemistry*
  • Dopamine Antagonists / pharmacology*
  • Humans
  • Ligands
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Radioligand Assay
  • Receptors, Dopamine D3 / antagonists & inhibitors*
  • Receptors, Dopamine D3 / metabolism
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Structure-Activity Relationship

Substances

  • Alkanes
  • Dopamine Antagonists
  • Ligands
  • Piperazines
  • Receptors, Dopamine D3
  • Spiro Compounds