New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments
Maria A. Lapshina,
Elena F. Shevtsova,
Vladimir V. Grigoriev,
Aleksey Yu. Aksinenko,
Aleksey A. Ustyugov,
Daniil A. Steinberg,
Grigoriy V. Maleev,
Elena S. Dubrovskaya,
Tatiana V. Goreva,
Tatiana A. Epishina,
Vladimir L. Zamoyski,
Galina F. Makhaeva,
Vladimir P. Fisenko,
Ivan M. Veselov,
Daria V. Vinogradova,
Sergey O. Bachurin
Affiliations
Maria A. Lapshina
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Elena F. Shevtsova
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Vladimir V. Grigoriev
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Aleksey Yu. Aksinenko
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Aleksey A. Ustyugov
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Daniil A. Steinberg
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Grigoriy V. Maleev
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Elena S. Dubrovskaya
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Tatiana V. Goreva
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Tatiana A. Epishina
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Vladimir L. Zamoyski
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Galina F. Makhaeva
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Vladimir P. Fisenko
Department of Pharmacology, Sechenov I. M. First Moscow State Medical University, 8 Build. 2 Trubetskaya Str., 119991 Moscow, Russia
Ivan M. Veselov
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Daria V. Vinogradova
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Sergey O. Bachurin
Institute of Physiologically Active Compounds at the Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 1 Severnij proezd, 142432 Chernogolovka, Russia
Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs—edaravone and riluzole—have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone—phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.
