Positive AMPA and Kainate Receptor Modulators and Their Therapeutic Potential in CNS Diseases: A Comprehensive Review

Ionotropic glutamate receptors-including N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors-play a pivotal role in excitatory signaling in the central nervous system (CNS), which is particularly important for learning and memory processes. Among them, AMPA and kainate receptors (known as 'non-NMDA' receptors) have gained increasing attention as therapeutic targets for various CNS disorders. Positive allosteric modulators (PAMs) of these receptors enhance their activity without directly activating them, offering a promising strategy to fine-tune glutamatergic signaling with potentially fewer side effects compared to orthosteric agonists. This review presents a comprehensive overview of recent advances in the development of AMPA and kainate receptor PAMs. We classify the most relevant modulators into main chemotype groups and discuss their binding modes, structure-activity relationships, and efficacy as determined through in vitro and in vivo studies. Additionally, we provide an overview of AMPA receptor PAMs that have entered into clinical trials over the past few decades. The increasing interest in kainate receptor PAMs is also mentioned, underlining their emerging role in future neuropharmacological strategies.