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

The synthetic approaches to three new AMPA receptor modulators-derivatives of 1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.13,11]tetradecane-4,8,12-trione-had been developed and all steps of synthesis were optimized. The structures of the compounds contain tricyclic cage and indane fragments necessary for binding with the target receptor. Their physiological activity was studied by radioligand-receptor binding analysis using [3H]PAM-43 as a reference ligand, which is a highly potent positive allosteric modulator of AMPA receptors. The results of radioligand-binding studies indicated the high potency of two synthesized compounds to bind with the same targets as positive allosteric modulator PAM-43 (at least on AMPA receptors). We suggest that the Glu-dependent specific binding site of [3H]PAM-43 or the receptor containing this site may be one of the targets of the new compounds. We also suggest that enhanced radioligand binding may indicate the existence of synergistic effects of compounds 11b and 11c with respect to PAM-43 binding to the targets. At the same time, these compounds may not compete directly with PAM-43 for its specific binding sites but bind to other specific sites of this biotarget, changing its conformation and thereby causing a synergistic effect of cooperative interaction. It can be expected that the newly synthesized compounds will also have pronounced effects on the glutamatergic system of the mammalian brain.

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

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.