Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug
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 agai...
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| Format: | Article |
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MDPI AG
2022-09-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/9/1108 |
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| author | Radoslav Chayrov Tatyana Volkova German Perlovich Li Zeng Zhuorong Li Martin Štícha Rui Liu Ivanka Stankova |
| author_facet | Radoslav Chayrov Tatyana Volkova German Perlovich Li Zeng Zhuorong Li Martin Štícha Rui Liu Ivanka Stankova |
| author_sort | Radoslav Chayrov |
| collection | DOAJ |
| description | 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 EC<sub>50</sub> 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. |
| first_indexed | 2024-03-09T22:51:50Z |
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| language | English |
| last_indexed | 2024-03-09T22:51:50Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj.art-f2390ac76cec401c803a98b591bd67ac2023-11-23T18:18:46ZengMDPI AGPharmaceuticals1424-82472022-09-01159110810.3390/ph15091108Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease DrugRadoslav Chayrov0Tatyana Volkova1German Perlovich2Li Zeng3Zhuorong Li4Martin Štícha5Rui Liu6Ivanka Stankova7Department of Chemistry, Faculty of Mathematics & Natural Sciences, South-West University “Neofit Rilski”, 2700 Blagoevgrad, BulgariaG.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, RussiaG.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, RussiaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaFaculty of Science, Charles University in Prague, 128 43 Prague, Czech RepublicInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaDepartment of Chemistry, Faculty of Mathematics & Natural Sciences, South-West University “Neofit Rilski”, 2700 Blagoevgrad, BulgariaGlutamate 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 EC<sub>50</sub> 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.https://www.mdpi.com/1424-8247/15/9/1108memantineglycinenootropicsneuroprotective actionsolubility |
| spellingShingle | Radoslav Chayrov Tatyana Volkova German Perlovich Li Zeng Zhuorong Li Martin Štícha Rui Liu Ivanka Stankova Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug Pharmaceuticals memantine glycine nootropics neuroprotective action solubility |
| title | Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug |
| title_full | Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug |
| title_fullStr | Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug |
| title_full_unstemmed | Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug |
| title_short | Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug |
| title_sort | synthesis neuroprotective effect and physicochemical studies of novel peptide and nootropic analogues of alzheimer disease drug |
| topic | memantine glycine nootropics neuroprotective action solubility |
| url | https://www.mdpi.com/1424-8247/15/9/1108 |
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