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Challenges for and current status of research into positive modulators of AMPA receptors

journal contribution
posted on 2023-06-07, 20:33 authored by Simon Ward, Benjamin D Bax, Mark Harries
AMPA receptors consist of a family of hetero-oligomeric (tetrameric) receptors arising from four genes, each of which encodes a distinct receptor subunit (GluA1-4). Recombinant homo-tetrameric AMPA receptors, comprising four identical subunits, are functionally active and have been used in in vitro assays. However, the many different subunit permutations make possible the functional and anatomical diversity of AMPA receptors throughout the CNS. Furthermore, AMPA receptor subunit stoichiometry influences the biophysical and functional properties of the receptor. A number of chemically diverse positive modulators of AMPA receptor have been identified which potentiate AMPA receptor-mediated activity in vitro as well as improving cognitive performance in rodents and non-human primates with several being taken further in the clinic. This review article summarizes the current status in the research on positive allosteric modulation of AMPA receptors and outlines the challenges involved in identifying a chemically distinct series of AMPA receptor positive modulators, addressing the challenges created by the heterogeneity of the AMPA receptor populations and the development of structure-activity relationships driven by homomeric, recombinant systems on high-throughput platforms. We also review the role of X-ray crystallography in the selection and prioritization of targets for lead optimization for AMPA receptor positive modulators.

History

Publication status

  • Published

Journal

British Journal of Pharmacology

ISSN

0007-1188

Issue

2

Volume

160

Page range

181-190

Pages

10.0

Department affiliated with

  • Chemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-02-06

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