SYNTHESIS AND MODULATORY ACTIVITY OF 3-ACETYL-7-(BENZOFURAN- 5-CARBONYL)-1,5-DIMETHYL-3,7-DIAZABICYCLO[3.3.1]NONAN-9-ONE ON AMPA RECEPTORS

Авторы

Ключевые слова:

3,7-diazabicyclo[3.3.1]nonanes, allosteric modulators, AMPA receptor, desymmetrization, monoacylation, neurodegenerative diseases, PAMs, patch clamp

Аннотация

3-Acetyl-7-(benzofuran-5-carbonyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one belonging to a previously unknown class of unsymmetrical N,N'-diacyl-substituted 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-ones has been synthesized. The key step in its synthesis involves a desymmetrization of the parent diamine by selective monoacetylation at a lower reaction temperature. In vitro assays by means of electrophysiological patch clamp technique revealed a high positive modulatory effect on the kainate-induced currents in Purkinje neurons in a wide concentration range from 10–11 to 10–6 M. Molecular dynamics simulations have confirmed the putative single and dual binding modes of the title compound in the positive allosteric modulator site of the AMPA (α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid) glutamate receptors. These results indicate that it could potentially serve as a lead compound for the development of broad-spectrum drugs for prevention and treatment of neurodegenerative diseases.

 

Биографии авторов

James Matthews, Department of Chemistry, Lomonosov Moscow State University

Department of Chemistry, Lomonosov Moscow State University,
1, Build. 3 Leninskie Gory, Moscow 119991, Russia

PhD student

Polina N. Veremeeva, Department of Chemistry, Lomonosov Moscow State University

Department of Chemistry, Lomonosov Moscow State University,
1, Build. 3 Leninskie Gory, Moscow 119991, Russia

Junior Researcher

Elena A. Golubeva, Department of Chemistry, Lomonosov Moscow State University

Department of Chemistry, Lomonosov Moscow State University,
1, Build. 3 Leninskie Gory, Moscow 119991, Russia

PhD student

Mstislav I. Lavrov, Department of Chemistry, Lomonosov Moscow State University

Department of Chemistry, Lomonosov Moscow State University,
1, Build. 3 Leninskie Gory, Moscow 119991, Russia

Senior Researcher

Eugene V. Radchenko, Department of Chemistry, Lomonosov Moscow State University

Department of Chemistry, Lomonosov Moscow State University,
1, Build. 3 Leninskie Gory, Moscow 119991, Russia

Associate Professor

Vladimir L. Zamoyski, Institute of Physiologically Active Compounds at Federal Research Centre of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Science

Institute of Physiologically Active Compounds at Federal Research Centre
of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences,
1 Severnyi Proezd, Chernogolovka 142432, Moscow Region, Russia

Leading researcher

Vladimir V. Grigoriev, Институт физиологически активных соединений Федерального исследовательского центра проблем химической физики и медицинской химии Российской академии наук

Institute of Physiologically Active Compounds at Federal Research Centre
of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences,
1 Severnyi Proezd, Chernogolovka 142432, Moscow Region, Russia

Head of laboratory, Chief researcher

Department of Chemistry, Lomonosov Moscow State University,
1, Build. 3 Leninskie Gory, Moscow 119991, Russia

Vladimir A. Palyulin, Department of Chemistry, Lomonosov Moscow State University

Department of Chemistry, Lomonosov Moscow State University,
1, Build. 3 Leninskie Gory, Moscow 119991, Russia

Head of the Laboratory, PhD, Leading Researcher

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Опубликован

2024-12-13

Выпуск

Том 60 № 9/10 (2024)

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