Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jan 18;24(3):1908.
doi: 10.3390/ijms24031908.

Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective

Paulina Chałupnik  1 , Ewa Szymańska  1
Affiliations
Review

Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective

Paulina Chałupnik et al. Int J Mol Sci. .

Abstract

Since the 1990s, ionotropic glutamate receptors have served as an outstanding target for drug discovery research aimed at the discovery of new neurotherapeutic agents. With the recent approval of perampanel, the first marketed non-competitive antagonist of AMPA receptors, particular interest has been directed toward 'non-NMDA' (AMPA and kainate) receptor inhibitors. Although the role of AMPA receptors in the development of neurological or psychiatric disorders has been well recognized and characterized, progress in understanding the function of kainate receptors (KARs) has been hampered, mainly due to the lack of specific and selective pharmacological tools. The latest findings in the biology of KA receptors indicate that they are involved in neurophysiological activity and play an important role in both health and disease, including conditions such as anxiety, schizophrenia, epilepsy, neuropathic pain, and migraine. Therefore, we reviewed recent advances in the field of competitive and non-competitive kainate receptor antagonists and their potential therapeutic applications. Due to the high level of structural divergence among the compounds described here, we decided to divide them into seven groups according to their overall structure, presenting a total of 72 active compounds.

Keywords: CNS diseases; antagonist; chronic pain; epilepsy; glutamate ionotropic receptors; kainate receptors; neurological diseases.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Canonical and non-canonical signaling of KARs (adapted from refs. [4,20]).
Figure 2
Figure 2
(A) Cryo-EM structure of the GluK2/5 heterotetramer in glutamate (l-Glu) bound state (PDB code: 7KS3); (B) cryo-EM structure of the GluK2/5 heterotetramer in the 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) bound state (PDB code: 7KS0); (C) cryo-EM structure of homotetrameric GluK2 in complex with NETO2 and DNQX, NETO2 shown in dark blue (PDB code: 7F5A).
Figure 3
Figure 3
Structures of selected KAR antagonists based on the quinoxaline-2,3-dione structure.
Figure 4
Figure 4
Structures of selected willardiine-based KAR antagonists. * the stereoisomeric center in the molecule.
Figure 5
Figure 5
Structures of cis-decahydroisoquinoline-derived KAR antagonists.
Figure 6
Figure 6
Structures of selected α-amino acid antagonists of kainate receptors. * the stereoisomeric center in the molecule.
Figure 7
Figure 7
Structurally dissimilar AMPAR/KAR antagonists.
Figure 8
Figure 8
Non-competitive antagonists and channel blockers of kainate receptors.
Figure 9
Figure 9
Common strategies in chemical modifications of RNA aptamers (adapted from ref. [217]).
See this image and copyright information in PMC

References

    1. Willard S.S., Koochekpour S. Glutamate, glutamate receptors, and downstream signaling pathways. Int. J. Biol. Sci. 2013;9:948–959. doi: 10.7150/ijbs.6426. - DOI - PMC - PubMed
    1. Hansen K.B., Wollmuth L.P., Bowie D., Furukawa H., Menniti F.S., Sobolevsky A.I., Swanson G.T., Swanger S.A., Greger I.H., Nakagawa T., et al. Structure, function, and pharmacology of glutamate receptor ion channels. Pharmacol. Rev. 2021;73:298–487. doi: 10.1124/pharmrev.120.000131. - DOI - PMC - PubMed
    1. Traynelis S.F., Wollmuth L.P., McBain C.J., Menniti F.S., Vance K.M., Ogden K.K., Hansen K.B., Yuan H., Myers S.J., Dingledine R. Glutamate receptor ion channels: Structure, regulation, and function. Pharmacol. Rev. 2010;62:405–496. doi: 10.1124/pr.109.002451. - DOI - PMC - PubMed
    1. Valbuena S., Lerma J. Non-canonical signaling, the hidden life of ligand-gated ion channels. Neuron. 2016;92:316–329. doi: 10.1016/j.neuron.2016.10.016. - DOI - PubMed
    1. Negrete-Díaz J.V., Sihra T.S., Flores G., Rodríguez-Moreno A. Non-canonical mechanisms of presynaptic kainate receptors controlling glutamate release. Front. Mol. Neurosci. 2018;11:128. doi: 10.3389/fnmol.2018.00128. - DOI - PMC - PubMed