Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug

Radoslav Chayrov; Tatyana Volkova; German Perlovich; Li Zeng; Zhuorong Li; Martin Štícha; Rui Liu; Ivanka Stankova

doi:10.3390/ph15091108

Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug

Pharmaceuticals (Basel). 2022 Sep 5;15(9):1108. doi: 10.3390/ph15091108.

Authors

Radoslav Chayrov¹, Tatyana Volkova², German Perlovich², Li Zeng³, Zhuorong Li³, Martin Štícha⁴, Rui Liu³, Ivanka Stankova¹

Affiliations

¹ Department of Chemistry, Faculty of Mathematics & Natural Sciences, South-West University "Neofit Rilski", 2700 Blagoevgrad, Bulgaria.
² G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, Russia.
³ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
⁴ Faculty of Science, Charles University in Prague, 128 43 Prague, Czech Republic.

Abstract

Glutamate is an excitatory neurotransmitter in the nervous system. Excessive glutamate transmission can lead to increased calcium ion expression, related to increased neurotoxicity. Memantine is used for treating patients with Alzheimer's disease (AD) due to its protective action on the neurons against toxicity caused by over activation of N-methyl-D-aspartate receptors. Nootropics, also called "smart drugs", are used for the treatment of cognitive deficits. In this work, we evaluate the neuroprotective action of four memantine analogues of glycine derivatives, including glycyl-glycine, glycyl-glycyl-glycine, sarcosine, dimethylglycine and three conjugates with nootropics, modafinil, piracetam and picamilon. The new structural memantine derivatives improved cell viability against copper-induced neurotoxicity in APPswe cells and glutamate-induced neurotoxicity in SH-SY5Y cells. Among these novel compounds, modafinil-memantine, piracetam-memantine, sarcosine-memantine, dimethylglycine-memantine, and glycyl-glycine-memantine were demonstrated with good EC₅₀ values of the protective effects on APPswe cells, accompanied with moderate amelioration from glutamate-induced neurotoxicity. In conclusion, our study demonstrated that novel structural derivatives of memantine might have the potential to develop promising lead compounds for the treatment of AD. The solubility of memantine analogues with nootropics and memantine analogues with glycine derivatives in buffer solutions at pH 2.0 and pH 7.4 simulating the biological media at 298.15 K was determined and the mutual influence of the structural fragments in the molecules on the solubility behavior was analyzed. The significative correlation equations relating the solubility and biological properties with the structural HYBOT (Hydrogen Bond Thermodynamics) descriptors were derived. These equations would greatly simplify the task of the directed design of the memantine analogues with improved solubility and enhanced bioavailability.

Keywords: glycine; memantine; neuroprotective action; nootropics; solubility.

Grants and funding

This research was funded by Bulgarian National Science Fund (BNSF), grant number KP-06-Russia/7-2019. This work was supported by the Russian Foundation for Basic Research for Russian-Bulgarian collaboration (project No. 19-53-18003).