Kainate Receptor Allosteric Modulators: State of the Art and Future Directions.

allosteric modulation; kainate receptors; positive and negative modulators; structure‐guided drug design; subunit selectivity; Kainic Acid Receptors; Allosteric Regulation/drug effects; Humans; Animals; Structure-Activity Relationship; Molecular Structure; Kainic Acid Receptors/metabolism; Kainic Acid Receptors/antagonists & inhibitors; Kainic Acid Receptors/agonists; Kainic Acid Receptors/chemistry

Abstract :

[en] Kainate receptors (KARs) are under-explored ionotropic glutamate receptors with growing interest as therapeutic targets in disorders involving dysregulated glutamatergic signaling. Allosteric modulation of KARs represents an attractive drug discovery strategy, enabling fine control of receptor activity without competing with glutamate at the orthosteric site. This review summarizes current knowledge on positive (KARPAMs) and negative (KARNAMs) allosteric modulators of KARs, integrating recent structural and pharmacological insights. We describe the limited set of known modulators, including BPAM344, BPAM521, endogenous tuning ions, lectins, galectins, perampanel, and selected AMPA-derived compounds, with emphasis on their binding sites, mechanisms of action, and selectivity profiles. Finally, we highlight the critical lack of truly subunit-selective KAR modulators and discuss how recent structural advances can enable rational design of next-generation chemical probes and drug candidates targeting KARs.

Disciplines :

Pharmacy, pharmacology & toxicology
Chemistry

Author, co-author :

Colson, Thomas ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique

Pirotte, Bernard ; Université de Liège - ULiège > Département de pharmacie

Francotte, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique

Language :

English

Title :

Kainate Receptor Allosteric Modulators: State of the Art and Future Directions.

Publication date :

15 June 2026

Journal title :

ChemMedChem

ISSN :

1860-7179

eISSN :

1860-7187

Publisher :

Wiley, Germany

Volume :

Issue :

Pages :

e70318

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://chemistry-europe.onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.70318

Funders :

Fonds De La Recherche Scientifique - FNRS
Fondation Léon Fredericq

Available on ORBi :

since 05 June 2026

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