Obiekt
Tytuł: Design and synthesis of modified amino acid derivatives with potential antiseizure and antinociceptice activity
Abstrakt:
Epilepsy is one of the most common neurological disorders, affecting approximately 1-2% of the population. It is characterized by a very complex pathophysiology and multifactorial etiology. The main form of treatment for most patients with epilepsy is pharmacotherapy. Despite the introduction of many new antiseizure medications in the last 20 years, about one third of patients do not respond to available therapies and suffer from drug-resistant epilepsy. Therefore, there is still an unmet need to develop new substances with a broad spectrum of action and a better safety profile, which would be effective in the treatment of drug-resistant seizures, modifying the the disease, and also inhibiting the process of epileptogenesis. The main goal of own research was to obtain new series of hybrid amino acid derivatives, which are structurally functionalized derivatives of α-alanine and phenylglycine with an acyclic structure, i.e. compounds in which the pyrrolidine-2,5-dione ring was replaced by acyl substituents. It is worth mentioning, that the pyrrolidine-2,5-dione group was a crucial structural fragment for the activity of hybrid compounds identified in previous studies, which were characterized by broad-spectrum of antiseizure activity in mouse models. The aforementioned modification allowed us to bring the structure of the new derivatives closer to the structure of lacosamide, wh ; ich is one of the newest antiseizure medication. Due to the strong protective effect of lacosamide in models of seizures induced by an electric current, it was assumed that the obtained compounds would be active in the maximal electroshock test (MES) and 6 Hz (32 mA and 44 mA). Further modifications consisted in obtaining derivatives containing a pyrrolidin-2-one ring (levetiracetam analogues) and referring in their structure to known TRPV1 channel antagonists. Moreover, considering the fact that chirality is an extremely important property of a molecule that can affect activity or toxicity, individual enantiomers were obtained for compounds with the strongest antiseizure activity. As part of the conducted chemical studies, a library of 76 original and structurally diverse chemical compounds was obtained, the synthesis of which required the preparation of 150 intermediate products. In in vivo pharmacological studies (mice, i.p.), 25 compounds were characterized by a broad-spectrum of activity in two animal seizure models (MES and 6 Hz [32 mA]), and 12 of them also in the 6 Hz drug-resistant seizure model (44 mA). Additionally, the most active substances were identified in the group of phenylglycine derivatives (i.e. enantiomers (R)-96 and (R)-111) and α-alanine (i.e. racemate 139, as well as its two enantiomers - (R)-168 and (S)-168). Selected compounds were also tested in the ; ivPTZ test and in the pentylenetetrazole-induced kindling model, after which the expression of neurotrophic factors such as mBDNF and NGF in the hippocampus and cerebral cortex of mice, as well as the level of glutamate and GABA, were examined. It should be emphasized that the obtained derivatives also possess strong antinociceptive effects in the formalin-induced tonic pain model, in capsaicin-induced pain, and in the oxaliplatin- and streptozotocin-induced neuropathic pain model in mice. In vitro studies conducted in the group of phenylglycine derivatives revealed that these compounds act through a multidirectional mechanism - in addition to blocking the TRPV1 channel, they also inhibited calcium and sodium currents at a concentration of 10 μM. In turn, for α-alanine derivatives, electrophysiological studies using the patch-clamp method showed that these substances inhibit fast sodium currents at the same concentration (10 μM). The favorable drug-like properties of the leading compounds were also confirmed by further studies including the assessment of the pharmacokinetic profile, as well as ADME-Tox (i.e. high metabolic stability on human liver microsomes, weak effect on CYPs, no hepatotoxicity, neurotoxicity, etc.). The results of research became the subject of Polish patent application No. P.447254 filed with the Patent Office of the Republic of Poland on December 22, 2023 ; .
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Rada Dyscypliny Nauki farmaceutyczne
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Data ostatniej modyfikacji:
24 kwi 2025
Data dodania obiektu:
24 kwi 2025
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http://dl.bm.cm-uj.krakow.pl:8080/publication/5250
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| Nazwa wydania | Data |
|---|---|
| ZB-142295 | 24 kwi 2025 |
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