Progress in the discovery of small molecule modulators of the Cys-loop superfamily receptors

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3207-3218. doi: 10.1016/j.bmcl.2017.04.073. Epub 2017 May 4.

Abstract

The vertebrate Cys-loop family of ligand-gated ion channels (LGICs) are comprised of nicotinic acetylcholine (nAChR), serotonin type 3 (5-HT3R), γ-aminobutyric acid (GABAAR), and glycine (GlyR) receptors. Here, we review efforts to discover selective small molecules targeting one or more Cys-loop receptors, with a focus on state-of-the-art modulators that have been reported over the past five years. Several highlighted compounds offer robust oral bioavailability and central exposure and have thus been useful in delineating pharmacokinetic/pharmacodynamic relationships in pre-clinical disease models. Others offer high levels of subtype and/or inter-superfamily selectivity and have facilitated understanding of complex SAR and pharmacodynamics.

Keywords: Cys-loop receptors; Glycine receptors; Ligand-gated ion channels; Nicotinic acetylcholine receptors; Serotonin type 3 receptors; γ-Aminobutyric acid receptor.

Publication types

  • Review

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Cysteine Loop Ligand-Gated Ion Channel Receptors / agonists*
  • Cysteine Loop Ligand-Gated Ion Channel Receptors / antagonists & inhibitors*
  • Cysteine Loop Ligand-Gated Ion Channel Receptors / chemistry
  • Cysteine Loop Ligand-Gated Ion Channel Receptors / metabolism
  • Drug Discovery
  • Humans
  • Models, Molecular
  • Small Molecule Libraries / administration & dosage
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacokinetics
  • Small Molecule Libraries / pharmacology*

Substances

  • Cysteine Loop Ligand-Gated Ion Channel Receptors
  • Small Molecule Libraries