A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke
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
Affiliations
Denis A. Borozdenko
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Aiarpi A. Ezdoglian
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Tatiana A. Shmigol
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Darya I. Gonchar
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Dmitri N. Lyakhmun
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Dmitri V. Tarasenko
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Yaroslav V. Golubev
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Elvira A. Cherkashova
Department 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, Russia
Daria D. Namestnikova
Department 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, Russia
Ilya L. Gubskiy
Department 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, Russia
Alexey A. Lagunin
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Leonid V. Gubsky
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Vladimir P. Chekhonin
Department of Medical Nanobiotechnologies, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Sophia S. Borisevich
Laboratory of Physical Chemistry, Ufa Institute of Chemistry UFRS RAS, pr. Oktyabrya 71, 450054 Ufa, Russia
Maxim A. Gureev
Laboratory of Bioinformatics, Research Center “Digital Biodesign and Personalized Healthcare”, I.M. Sechenov University, 119991 Moscow, Russia
Anastasia D. Shagina
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Nina M. Kiseleva
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Vadim V. Negrebetsky
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
Yuri I. Baukov
Department of Medicinal Chemistry and Toxicology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
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 1) 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 1, 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 1 is capable of crossing the blood–brain barrier in intact and ischemic animals. Compound 1 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 1 could affect the AMPA receptor function. In a rat model of acute focal cerebral ischemia, we studied the effects of compound 1 on the behavior and neurological deficit. An in vivo experiment demonstrated that compound 1 significantly reduced the neurological deficit and improved neurological symptom regression, exploratory behavior, and anxiety. Thus, here, for the first time, we show that compound 1 can be considered as an agent for restoring cognitive functions.