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Identification of Positive Allosteric Modulators of Glycine Receptors from a High-Throughput Screen Using a Fluorescent Membrane Potential Assay.

Authors
  • Stead, Clara1
  • Brown, Adam1
  • Adams, Cathryn1
  • Nickolls, Sarah J1
  • Young, Gareth1
  • Kammonen, Juha1
  • Pryde, David1
  • Cawkill, Darren1
  • 1 1 Neusentis (Pfizer Ltd.), Granta Park, Great Abington, Cambridgeshire, UK.
Type
Published Article
Journal
Journal of biomolecular screening
Publication Date
Dec 01, 2016
Volume
21
Issue
10
Pages
1042–1053
Identifiers
DOI: 10.1177/1087057116657779
PMID: 27412533
Source
Medline
Keywords
License
Unknown

Abstract

Glycine receptor 3 (GlyRα3) is a ligand-gated ion channel of the cys-loop family that plays a key role in mediating inhibitory neurotransmission and regulation of pain signaling in the dorsal horn. Potentiation of GlyRα3 function is therefore of interest as a putative analgesic mechanism with which to target new therapeutics. However, to date, positive allosteric modulators (PAMs) of this receptor with sufficient selectivity to enable target validation studies have not been described. To address this lack of pharmacological tools, we developed a suite of in vitro assays comprising a high-throughput fluorescent membrane potential screen and a medium-throughput electrophysiology assay using IonFlux HT together with conventional manual patch clamp. Using these assays, we conducted a primary screening campaign and report the structures of hit compounds identified as GlyR PAMs. Our functional characterization data reveal a hit compound with high efficacy relative to current known potentiators and selectivity over GABAAR, another major class of inhibitory neurotransmission receptors of importance to pain. These small-molecule GlyR PAMs have high potential both as early tool compounds to enable pharmacological studies of GlyR inhibitory neurotransmission and as a starting point for the development of potent, selective GlyRα3 PAMs as novel analgesics.

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