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New Allosteric Modulators of AMPA Receptors: Synthesis and Study of Their Functional Activity by Radioligand-Receptor Binding Analysis.
Golubeva, Elena A; Lavrov, Mstislav I; Veremeeva, Polina N; Vyunova, Tatiana V; Shevchenko, Konstantin V; Topchiy, Maxim A; Asachenko, Andrey F; Palyulin, Vladimir A.
Afiliación
  • Golubeva EA; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
  • Lavrov MI; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
  • Veremeeva PN; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
  • Vyunova TV; Laboratory of Molecular Pharmacology of Peptides, Institute of Molecular Genetics, National Research Centre Kurchatov Institute, 123182 Moscow, Russia.
  • Shevchenko KV; Laboratory of Molecular Pharmacology of Peptides, Institute of Molecular Genetics, National Research Centre Kurchatov Institute, 123182 Moscow, Russia.
  • Topchiy MA; A.V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 119991 Moscow, Russia.
  • Asachenko AF; A.V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 119991 Moscow, Russia.
  • Palyulin VA; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
Int J Mol Sci ; 24(12)2023 Jun 18.
Article en En | MEDLINE | ID: mdl-37373440
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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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Receptores AMPA / Mamíferos Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Receptores AMPA / Mamíferos Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article