A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke
We performed an in silico, in vitro, and in vivo assessment of a potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (compound <b>1</b>) as a potential prodrug for cognitive function improvement in ischemic brain injury. Using in silico methods, we predicted the phar...
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MDPI AG
2021-10-01
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| author | Denis A. Borozdenko Aiarpi A. Ezdoglian Tatiana A. Shmigol Darya I. Gonchar Dmitri N. Lyakhmun Dmitri V. Tarasenko Yaroslav V. Golubev Elvira A. Cherkashova Daria D. Namestnikova Ilya L. Gubskiy Alexey A. Lagunin Leonid V. Gubsky Vladimir P. Chekhonin Sophia S. Borisevich Maxim A. Gureev Anastasia D. Shagina Nina M. Kiseleva Vadim V. Negrebetsky Yuri I. Baukov |
| author_facet | Denis A. Borozdenko Aiarpi A. Ezdoglian Tatiana A. Shmigol Darya I. Gonchar Dmitri N. Lyakhmun Dmitri V. Tarasenko Yaroslav V. Golubev Elvira A. Cherkashova Daria D. Namestnikova Ilya L. Gubskiy Alexey A. Lagunin Leonid V. Gubsky Vladimir P. Chekhonin Sophia S. Borisevich Maxim A. Gureev Anastasia D. Shagina Nina M. Kiseleva Vadim V. Negrebetsky Yuri I. Baukov |
| author_sort | Denis A. Borozdenko |
| collection | DOAJ |
| description | We performed an in silico, in vitro, and in vivo assessment of a potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (compound <b>1</b>) as a potential prodrug for cognitive function improvement in ischemic brain injury. Using in silico methods, we predicted the pharmacological efficacy and possible safety in rat models. In addition, in silico data showed neuroprotective features of compound <b>1</b>, which were further supported by in vitro experiments in a glutamate excitotoxicity-induced model in newborn rat cortical neuron cultures. Next, we checked whether compound <b>1</b> is capable of crossing the blood–brain barrier in intact and ischemic animals. Compound <b>1</b> improved animal behavior both in intact and ischemic rats and, even though the concentration in intact brains was low, we still observed a significant anxiety reduction and activity escalation. We used molecular docking and molecular dynamics to support our hypothesis that compound <b>1</b> could affect the AMPA receptor function. In a rat model of acute focal cerebral ischemia, we studied the effects of compound <b>1</b> on the behavior and neurological deficit. An in vivo experiment demonstrated that compound <b>1</b> significantly reduced the neurological deficit and improved neurological symptom regression, exploratory behavior, and anxiety. Thus, here, for the first time, we show that compound <b>1</b> can be considered as an agent for restoring cognitive functions. |
| first_indexed | 2024-03-10T06:20:51Z |
| format | Article |
| id | doaj.art-2b3a5471b2ee494e851c618e38e99ac8 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T06:20:51Z |
| publishDate | 2021-10-01 |
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| series | Molecules |
| spelling | doaj.art-2b3a5471b2ee494e851c618e38e99ac82023-11-22T19:18:28ZengMDPI AGMolecules1420-30492021-10-012620612410.3390/molecules26206124A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic StrokeDenis A. Borozdenko0Aiarpi A. Ezdoglian1Tatiana A. Shmigol2Darya I. Gonchar3Dmitri N. Lyakhmun4Dmitri V. Tarasenko5Yaroslav V. Golubev6Elvira A. Cherkashova7Daria D. Namestnikova8Ilya L. Gubskiy9Alexey A. Lagunin10Leonid V. Gubsky11Vladimir P. Chekhonin12Sophia S. Borisevich13Maxim A. Gureev14Anastasia D. Shagina15Nina M. Kiseleva16Vadim V. Negrebetsky17Yuri I. Baukov18Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaDepartment of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaDepartment of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaDepartment of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaDepartment of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaDepartment of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaDepartment of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaDepartment of Neurology, Neurosurgery and Medical Genetics, Faculty of Medicine Federal State Budgetary Institution, Federal Center of Brain Research and Neurotechnologies, Federal Medical Bio-logical Agency, 117997 Moscow, RussiaDepartment of Neurology, Neurosurgery and Medical Genetics, Faculty of Medicine Federal State Budgetary Institution, Federal Center of Brain Research and Neurotechnologies, Federal Medical Bio-logical Agency, 117997 Moscow, RussiaDepartment of Neurology, Neurosurgery and Medical Genetics, Faculty of Medicine Federal State Budgetary Institution, Federal Center of Brain Research and Neurotechnologies, Federal Medical Bio-logical Agency, 117997 Moscow, RussiaDepartment of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaDepartment of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaDepartment of Medical Nanobiotechnologies, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaLaboratory of Physical Chemistry, Ufa Institute of Chemistry UFRS RAS, pr. Oktyabrya 71, 450054 Ufa, RussiaLaboratory of Bioinformatics, Research Center “Digital Biodesign and Personalized Healthcare”, I.M. Sechenov University, 119991 Moscow, RussiaDepartment of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaDepartment of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaDepartment of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaDepartment of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaWe performed an in silico, in vitro, and in vivo assessment of a potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (compound <b>1</b>) as a potential prodrug for cognitive function improvement in ischemic brain injury. Using in silico methods, we predicted the pharmacological efficacy and possible safety in rat models. In addition, in silico data showed neuroprotective features of compound <b>1</b>, which were further supported by in vitro experiments in a glutamate excitotoxicity-induced model in newborn rat cortical neuron cultures. Next, we checked whether compound <b>1</b> is capable of crossing the blood–brain barrier in intact and ischemic animals. Compound <b>1</b> improved animal behavior both in intact and ischemic rats and, even though the concentration in intact brains was low, we still observed a significant anxiety reduction and activity escalation. We used molecular docking and molecular dynamics to support our hypothesis that compound <b>1</b> could affect the AMPA receptor function. In a rat model of acute focal cerebral ischemia, we studied the effects of compound <b>1</b> on the behavior and neurological deficit. An in vivo experiment demonstrated that compound <b>1</b> significantly reduced the neurological deficit and improved neurological symptom regression, exploratory behavior, and anxiety. Thus, here, for the first time, we show that compound <b>1</b> can be considered as an agent for restoring cognitive functions.https://www.mdpi.com/1420-3049/26/20/6124synthesisneuroprotective activitytransient MCAOexperimental ischemic strokebehavioral tests |
| spellingShingle | Denis A. Borozdenko Aiarpi A. Ezdoglian Tatiana A. Shmigol Darya I. Gonchar Dmitri N. Lyakhmun Dmitri V. Tarasenko Yaroslav V. Golubev Elvira A. Cherkashova Daria D. Namestnikova Ilya L. Gubskiy Alexey A. Lagunin Leonid V. Gubsky Vladimir P. Chekhonin Sophia S. Borisevich Maxim A. Gureev Anastasia D. Shagina Nina M. Kiseleva Vadim V. Negrebetsky Yuri I. Baukov A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke Molecules synthesis neuroprotective activity transient MCAO experimental ischemic stroke behavioral tests |
| title | A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke |
| title_full | A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke |
| title_fullStr | A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke |
| title_full_unstemmed | A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke |
| title_short | A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke |
| title_sort | novel phenylpyrrolidine derivative synthesis and effect on cognitive functions in rats with experimental ishemic stroke |
| topic | synthesis neuroprotective activity transient MCAO experimental ischemic stroke behavioral tests |
| url | https://www.mdpi.com/1420-3049/26/20/6124 |
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