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

• Published in: International journal of molecular sciences Vol. 24; no. 12; p. 10293
• Main Authors: Golubeva, Elena A, Lavrov, Mstislav I, Veremeeva, Polina N, Vyunova, Tatiana V, Shevchenko, Konstantin V, Topchiy, Maxim A, Asachenko, Andrey F, Palyulin, Vladimir A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.06.2023; MDPI
• Subjects: [3H]PAM-43; Allosteric properties; Allosteric Regulation; Allosteric Site; Alzheimer's disease; AMPA receptor allosteric modulators; Animals; Binding Sites; CNS pathologies; Conformation; cross-coupling reaction; Glutamatergic transmission; heterogeneous hydrogenation; Hydrogenation; Ligands; Mammals; Neurophysiology; Optimization; Pharmacokinetics; Protein Binding; radioligand binding; Receptors, AMPA - chemistry; Synergistic effect; Tetradecane; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; Russia; radioligand binding; cross-coupling reaction; AMPA receptor allosteric modulators; [3H]PAM-43; heterogeneous hydrogenation; CNS pathologies
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241210293

The synthetic approaches to three new AMPA receptor modulators-derivatives of 1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.1 ]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 [ H]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 [ H]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 and 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.