New 1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.13,11]tetradecane-4,8,12-trione derivative as an allosteric modulator of the glutamatergic system

Golubeva, Elena A.; Lavrov, Mstislav I.; Veremeeva, Polina N.; Bovina, Evgenia M.; Radchenko, Eugene V.; Topchiy, Maxim A.; Asachenko, Andrey F.; Zamoyski, Vladimir L.; Grigoriev, V. V.; Palyulin, Vladimir A.

doi:10.1016/j.mencom.2023.01.022

Cited by 4 publications

(1 citation statement)

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“…As a result of these studies, new potential allosteric modulators based on a bispidine moiety-containing tricyclic scaffold were developed. In particular, the derivatives of 1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.1 3,11 ]tetradecane-4,8,12-trione in electrophysiological studies using the patch clamp technique, showed pronounced modulatory effects (both positive and negative) in subnanomolar concentrations with respect to AMPA receptors [35][36][37][38][39]. An important advantage of both positive and negative allosteric modulators of AMPA receptors is that they suppress the process of desensitization-the inability of the receptor to re-transit into an activated state, despite the presence of an agonist.…”

Section: Introductionmentioning

confidence: 99%

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

Golubeva

Lavrov

Veremeeva

et al. 2023

IJMS

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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.

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