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

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.