Diversity of AMPA Receptor Ligands: Chemotypes, Binding Modes, Mechanisms of Action, and Therapeutic Effects

Abstract

L-Glutamic acid is the main excitatory neurotransmitter in the central nervous system (CNS). Its associated receptors localized on neuronal and non-neuronal cells mediate rapid excitatory synaptic transmission in the CNS and regulate a wide range of processes in the brain, spinal cord, retina, and peripheral nervous system. In particular, the glutamate receptors selective to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) also play an important role in numerous neurological disorders and attract close attention as targets for the creation of new classes of drugs for the treatment or substantial correction of a number of serious neurodegenerative and neuropsychiatric diseases. For this reason, the search for various types of AMPA receptor ligands and studies of their properties are attracting considerable attention both in academic institutions and in pharmaceutical companies around the world. This review focuses mainly on the advances in this area published since 2017. Particular attention is paid to the structural diversity of new chemotypes of agonists, competitive AMPA receptor antagonists, positive and negative allosteric modulators, transmembrane AMPA regulatory protein (TARP) dependent allosteric modulators, ion channel blockers as well as their binding sites. This review also presents the studies of the mechanisms of action of AMPA receptor ligands that mediate their therapeutic effects.

New Allosteric Modulators of AMPA Receptors: Synthesis and Study of Their Functional Activity by Radioligand-Receptor Binding Analysis

“…Both compounds have demonstrated a significant increase in PAM-43 binding. According to the available data, AMPA receptors have multiple binding sites [ 60 ], so we can suppose that the binding sites of compounds 11b and 11c in the receptors at least partially do not coincide with the binding sites of PAM-43, however binding of these compounds leads to a pronounced synergistic increase in PAM-43 binding. That confirms that biotargets of new compounds and biotargets of PAM-43 are interrelated.…”

Acute ampakines increase voiding function and coordination in a rat model of SCI

“…Positive allosteric modulators have been shown to bind at the interface between two adjacent subunits at the D1 lobe of the ligand-binding domain ( Jin et al, 2005 ). Alternative splicing of amino acids at the ligand-binding domain of various receptor subunits can change the domain interface, thereby changing the interaction of allosteric modulators and how they impact channel kinetics and their sensitivity ( Golubeva et al, 2022 ). Based on current data, we presume that ampakines act similarly on various AMPA receptor subunits.…”

Electrophysiological Assessment of Newly Synthesized 2,3-Benzodiazepine Derivatives for Inhibiting the AMPA Receptor Channel

“…Finally, acknowledging individual variability in response, including genetic variations and comorbidities, underscores the importance of personalized treatment strategies in clinical settings. Addressing these considerations will advance the therapeutic potential of 2,3-BDZ, paving the way for more effective and targeted interventions in neurological disorders [ 43 , 44 , 45 ].…”