Therapeutic potential of positive allosteric modulators of AMPA receptors in brain disorders.

Abstract

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA receptors) are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. By translating chemical signals into rapid electrical depolarization, AMPA receptors, together with NMDA and kainate receptors, coordinate synaptic plasticity at glutamatergic synapses, thereby shaping learning, memory, and higher-order cognitive functions. Neurological disorders characterized by glutamatergic dysfunction represent a major clinical challenge, largely because pharmacological targeting of this system requires a delicate balance between efficacy and adverse effects. Accordingly, the clinical development of direct AMPA receptor agonists and antagonists has been hampered by poor tolerability and the risk of neurotoxicity; to date, only the non-competitive antagonist perampanel has reached clinical use. This therapeutic gap highlights the compelling need to develop safer, more tolerable, and reversible drug candidates capable of modulating synaptic plasticity in disorders characterized by glutamatergic impairment. Within this framework, AMPA receptor allosteric modulators have attracted attention as a promising alternative to direct ligands. Specifically, positive allosteric modulators, or AMPAkines, represent a potentially favourable therapeutic compromise because they facilitate receptor activation while preserving physiological receptor kinetics. Accordingly, this narrative review examines the therapeutic potential of AMPAkines in neurodegenerative and neurodevelopmental disorders and provides a comprehensive overview of their progress in preclinical and clinical studies.