A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke

Abstract

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.

The Effect of a New N-hetero Cycle Derivative on Behavior and Inflammation against the Background of Ischemic Stroke

“…Transient Middle Cerebral Artery Occlusion was conducted as previously described [ 17 ]. The rats were anesthetized initially using 3% isoflurane and maintained with a mixture of 2–2.5% isoflurane and 97.5–98% atmospheric air (EZ-7000 Classic System, E-Z Anesthesia ® Systems).…”

“…Additionally these drugs affect memory processes. Previously, we carried out a chemical modification of Compound 2 by introducing a fragment of the potassium salt of taurine into its composition ( Scheme 1 , Compound 3 ) in order to increase the pharmacological efficacy in the treatment of post-stroke state in rats, as well as to obtain its water-soluble form suitable for the injection route of administration [ 17 ]. We have shown that Compound 3 better restores motor function and improves the cognitive abilities of animals in the post-stroke period, compared with the well-known water-soluble nootropic of the same class—piracetam (Compound 1 ).…”

Identification of cholest-4-ene-3,6-dione as a Novel Neuroprotectant in Ischemic Stroke and Its Lipidomics

“…D-glutamate-treated CGNs and cortical neuron (CN) death are also considered classical neuronal excitotoxicity models. 9 Finally, middle cerebral artery occlusion (MCAO) is the most widely used cerebral ischemia model at present. Its pathogenesis is similar to that of human ischemic stroke, which gives it great importance in simulating cerebral ischemia and drug screening.…”

Pyridine Carboxamides Based on Sulfobetaines: Design, Reactivity, and Biological Activity

“…For many years, our group has focused on discovering and developing new heterocyclic compounds that have nootropic, anti-inflammatory, and antidepressant activities. Our main goal is to develop effective medications for treating cognitive impairments, including ischemic stroke and its complications [ 1 , 2 , 3 , 4 ]. The recent COVID-19 pandemic highlighted the emerging need for these kinds of therapeutic agents.…”

“…One of the reasons is insufficient bioavailability and multiple side effects. Previously, we managed to increase the bioavailability of Phenotropil by introducing chemical modification, which led to the production of a water-soluble form based on taurine [ 1 ]. The same approach was shown for homotaurine [ 3 ].…”