Meditsinskiy sovet = Medical Council | 2021
Antiparkinsonian activity of new N-methyl-D-aspartate receptor ligands in the arecoline hyperkinesis test
Abstract
Introduction. Parkinson’s disease (PD) is one of\xa0the\xa0most common neurodegenerative diseases in\xa0the\xa0population of\xa0older patients. Even though long-term combination therapy helps to cope with the\xa0main\xa0manifestations of\xa0PD. It inevitably leads to the\xa0appearance of\xa0 such side effects as drowsiness, hallucinations, dyskinesia, and many others.\xa0 [12]. Therefore, the\xa0 search for\xa0 effective antiparkinsonian drugs devoid of\xa0the\xa0above-mentioned adverse reactions remains an urgent task of\xa0modern neuropharmacology.The\xa0explored substances are derivatives of\xa0imidazole-4,5-dicarboxylic acid. These compounds belong to a\xa0fundamentally new class of\xa0N-methyl-D-aspartate ligands (NMDA) that are not channel blockers. Their pharmacological effect is realized due to interaction with the\xa0NMDA\xa0receptor recognition site, which, along with high efficiency, allows us to assume their higher safety, compared to previously existing channel blockers from the\xa0NMDA\xa0ligand group.Objective. Studing of\xa0 the\xa0 antiparkinsonian activity of\xa0 new ligands of\xa0 the\xa0 glutamate NMDA-receptor complex-1,2-substituted imidazole-4,5-dicarboxylic acids on an experimental model of\xa0arecoline hyperkinesis.Materials and methods. Imidazole-dicarboxylic acid derivatives (IEM2258, IEM2248, IEM2247, and IEM1574) were injected into the\xa0lateral ventricles of\xa0the\xa0mouse brain\xa010\xa0minutes before arecoline in\xa0a\xa0volume of\xa05\xa0µl at doses of\xa00.1-0.5\xa0µmol, then the\xa0latent period, intensity, and duration of\xa0tremor were recorded. Amantadine was used as a\xa0comparison drug.Results. Preliminary administration of\xa0the\xa0studied examined substances led to a\xa0significant decrease in\xa0the\xa0intensity and duration of\xa0arecoline tremor. The\xa0highest inhibitory activity with respect to the\xa0intensity and duration of\xa0the\xa0experimental tremor was demonstrated with the\xa0introduction of\xa0the\xa0compound IEM-2247\xa0(at a\xa0dose of\xa00.1-0.5\xa0mmol, the\xa0duration of\xa0the\xa0latent period of\xa0the\xa0tremor was 1.7-2.3\xa0times longer than the\xa0control one, respectively, the\xa0duration of\xa0the\xa0tremor decreased by 1.5\xa0- 2.5\xa0times).Conclusions. The\xa0 dose-dependent antiparkinsonian activity of\xa0 imidazole-dicarboxylic acid derivatives is shown, indicating the prospects for the development of these substances and the further search for effective and safe antiparkinsonian agents among the compounds of this class.\xa0