Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands
A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-09-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/18/5527 |
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| author | Sergey O. Bachurin Galina F. Makhaeva Elena F. Shevtsova Alexey Yu. Aksinenko Vladimir V. Grigoriev Pavel N. Shevtsov Tatiana V. Goreva Tatiana A. Epishina Nadezhda V. Kovaleva Elena A. Pushkareva Natalia P. Boltneva Sofya V. Lushchekina Alexey V. Gabrelyan Vladimir L. Zamoyski Lyudmila G. Dubova Elena V. Rudakova Vladimir P. Fisenko Elena V. Bovina Rudy J. Richardson |
| author_facet | Sergey O. Bachurin Galina F. Makhaeva Elena F. Shevtsova Alexey Yu. Aksinenko Vladimir V. Grigoriev Pavel N. Shevtsov Tatiana V. Goreva Tatiana A. Epishina Nadezhda V. Kovaleva Elena A. Pushkareva Natalia P. Boltneva Sofya V. Lushchekina Alexey V. Gabrelyan Vladimir L. Zamoyski Lyudmila G. Dubova Elena V. Rudakova Vladimir P. Fisenko Elena V. Bovina Rudy J. Richardson |
| author_sort | Sergey O. Bachurin |
| collection | DOAJ |
| description | A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer’s disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure–activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced β-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action. |
| first_indexed | 2024-03-10T07:24:26Z |
| format | Article |
| id | doaj.art-b4963a08afd643abb60d9c73f498c6f7 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T07:24:26Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-b4963a08afd643abb60d9c73f498c6f72023-11-22T14:24:27ZengMDPI AGMolecules1420-30492021-09-012618552710.3390/molecules26185527Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional LigandsSergey O. Bachurin0Galina F. Makhaeva1Elena F. Shevtsova2Alexey Yu. Aksinenko3Vladimir V. Grigoriev4Pavel N. Shevtsov5Tatiana V. Goreva6Tatiana A. Epishina7Nadezhda V. Kovaleva8Elena A. Pushkareva9Natalia P. Boltneva10Sofya V. Lushchekina11Alexey V. Gabrelyan12Vladimir L. Zamoyski13Lyudmila G. Dubova14Elena V. Rudakova15Vladimir P. Fisenko16Elena V. Bovina17Rudy J. Richardson18Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaI.M.Sechenov First Moscow State Medical University, 8 Build. 2 Trubetskaya Str., 119991 Moscow, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaDepartment of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USAA new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer’s disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure–activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced β-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action.https://www.mdpi.com/1420-3049/26/18/5527multifunctional agentsAlzheimer’s diseasecholinesterasesNMDA receptormitochondrial permeability transition (MPT) poremicrotubules |
| spellingShingle | Sergey O. Bachurin Galina F. Makhaeva Elena F. Shevtsova Alexey Yu. Aksinenko Vladimir V. Grigoriev Pavel N. Shevtsov Tatiana V. Goreva Tatiana A. Epishina Nadezhda V. Kovaleva Elena A. Pushkareva Natalia P. Boltneva Sofya V. Lushchekina Alexey V. Gabrelyan Vladimir L. Zamoyski Lyudmila G. Dubova Elena V. Rudakova Vladimir P. Fisenko Elena V. Bovina Rudy J. Richardson Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands Molecules multifunctional agents Alzheimer’s disease cholinesterases NMDA receptor mitochondrial permeability transition (MPT) pore microtubules |
| title | Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands |
| title_full | Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands |
| title_fullStr | Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands |
| title_full_unstemmed | Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands |
| title_short | Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands |
| title_sort | conjugation of aminoadamantane and γ carboline pharmacophores gives rise to unexpected properties of multifunctional ligands |
| topic | multifunctional agents Alzheimer’s disease cholinesterases NMDA receptor mitochondrial permeability transition (MPT) pore microtubules |
| url | https://www.mdpi.com/1420-3049/26/18/5527 |
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