Positive allosteric modulators of AMPA receptors: advances and emerging trends

INTRODUCTION: AMPA receptors are key mediators of excitatory neurotransmission and attractive targets for central nervous system disorders. An updated review of AMPA receptor positive allosteric modulators is timely given recent medicinal chemistry advances and renewed translational interest. AREAS COVERED: This review summarizes the evolution from early high-impact, seizure-prone ampakines to more refined low- to intermediate-impact modulators based on sulfur-containing heterocycles and sulfonamide scaffolds. We discuss the main structural and functional determinants of AMPA receptor pharmacology, including the dimer-interface allosteric site, flip/flop splice variants, and auxiliary proteins such as TARPs. Key chemotypes covered include benzamides, benzothiadiazines, benzoxathiazines such as TAK-653 and LT-102, constrained sulfonamides such as PF-04958242, PF-4778574 and MDI-222, and newer heterocyclic and bivalent ligands. Literature was selected through a focused review of published medicinal chemistry, pharmacology, and translational studies relevant to AMPA receptor PAMs. EXPERT OPINION: AMPA receptor potentiation remains a promising strategy, but future candidates will need to combine potency, finely tuned efficacy, favorable pharmacokinetics, and circuit-level selectivity. The most successful next-generation PAMs will likely be those that maximize therapeutic window while minimizing seizure liability.