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

Golubeva, E.A.; Lavrov, M.I.; Veremeeva, P.N.; Vyunova, T.V.; Shevchenko, K.V.; Topchiy, M.A.; Asachenko, A.F.; Palyulin, V.A.

Статья опубликована в высокорейтинговом журнале

Информация о цитировании статьи получена из Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 20 февраля 2024 г.

Авторы: Golubeva Elena A., Lavrov Mstislav I., Veremeeva Polina N., Vyunova Tatiana V., Shevchenko Konstantin V., Topchiy Maxim A., Asachenko Andrey F., Palyulin Vladimir A.
Журнал: International Journal of Molecular Sciences
Том: 24
Номер: 12
Год издания: 2023
Издательство: MDPI
Местоположение издательства: Basel, Switzerland
Первая страница: 10293
DOI: 10.3390/ijms241210293
Аннотация: The synthetic approaches to three new AMPA receptor modulators—derivatives of1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.13,11]tetradecane-4,8,12-trione—had been developed and allsteps of synthesis were optimized. The structures of the compounds contain tricyclic cage and indanefragments necessary for binding with the target receptor. Their physiological activity was studiedby radioligand-receptor binding analysis using [3H]PAM-43 as a reference ligand, which is a highlypotent positive allosteric modulator of AMPA receptors. The results of radioligand-binding studiesindicated the high potency of two synthesized compounds to bind with the same targets as positiveallosteric modulator PAM-43 (at least on AMPA receptors). We suggest that the Glu-dependentspecific binding site of [3H]PAM-43 or the receptor containing this site may be one of the targets ofthe new compounds. We also suggest that enhanced radioligand binding may indicate the existenceof synergistic effects of compounds 11b and 11c with respect to PAM-43 binding to the targets. Atthe same time, these compounds may not compete directly with PAM-43 for its specific bindingsites but bind to other specific sites of this biotarget, changing its conformation and thereby causinga synergistic effect of cooperative interaction. It can be expected that the newly synthesized compoundswill also have pronounced effects on the glutamatergic system of the mammalian brain.
Добавил в систему: Лавров Мстислав Игоревич

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

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