From NMDA receptor antagonists to discovery of selective σ₂ receptor ligands

Bioorg Med Chem. 2014 Jan 1;22(1):393-7. doi: 10.1016/j.bmc.2013.11.014. Epub 2013 Nov 15.

Abstract

Following previous studies focused on the search for new molecules targeting GluN2B-containing NMDA, a small series of 1-(1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone derivatives has been synthesized by using Microwave Assisted Organic Synthesis (MAOS). Given that GluN2B ligands frequently exert off-target effects we also tested their affinity towards sigma receptors. Binding assay revealed that only the 1-(5-hydroxy-1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone (7a) retained GluN2B affinity. Interestingly, the 5-methoxyindoles 5a and 6a were efficient and selective ligands toward σ₂ receptor (Ki values of 10nM and 20 nM, respectively). Thus, in this case the discovery of new σ₂ receptor selective ligands was an unexpected result emerging from the screening of cross-activity against other CNS receptors.

Keywords: GluN2B/NMDA; Glutamate; Ifenprodil; Indoles; Sigma receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Glutamic Acid / metabolism*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, sigma / drug effects*
  • Receptors, sigma / metabolism
  • Structure-Activity Relationship

Substances

  • Receptors, N-Methyl-D-Aspartate
  • Receptors, sigma
  • Glutamic Acid