Phenylalanine derivatives with modulating effects on human α1-glycine receptors and anticonvulsant activity in strychnine-induced seizure model in male adult rats

Bassem Sadek, Murat Oz, Syed M. Nurulain, Petrilla Jayaprakash, Gniewomir Latacz, Katarzyna Kieć-Kononowicz, Ewa Szymańska

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

The critical role of α1-glycine receptor (α1-GLYRs) in pathological conditions such as epilepsy is well known. In the present study, structure-activity relations for a series of phenylalanine derivatives carrying selected hydrogen bond acceptors were investigated on the functional properties of human α1-GLYR expressed in Xenopus oocytes. The results indicate that one particular substitution position appeared to be of special importance for control of ligand activity. Among tested ligands (1-8), the biphenyl derivative (2) provided the most promising antagonistic effect on α1-GLYRs, while its phenylbenzyl analogue (5) exhibited the highest potentiation effect. Moreover, ligand 5 with most promising potentiating effect showed in-vivo moderate protection when tested in strychnine (STR)-induced seizure model in male adult rats, whereas ligand 2 with highest antagonistic effect failed to provide appreciable anti(pro)convulsant effect. Furthermore, ligands 2 and 5 with the most promising effects on human α1-GLYRs were examined for their toxicity and potential neuroprotective effect against neurotoxin 6-hydroxydopamine (6-OHDA). The results show that ligands 2 and 5 possessed neither significant antiproliferative effects, nor necrotic and mitochondrial toxicity (up to concentration of 50 μM). Moreover, ligand 2 showed weak neuroprotective effect at the 50 μM against 100 μM toxic dose of 6-OHDA. Our results indicate that modulatory effects of ligands 2 and 5 on human α1-GLYRs as well as on STR-induced convulsion can provide further insights for the design of therapeutic agents in treatment of epilepsy and other pathological conditions requiring enhanced activity of inhibitory glycine receptors.

Original languageEnglish
Pages (from-to)124-131
Number of pages8
JournalEpilepsy Research
Volume138
DOIs
Publication statusPublished - Dec 2017

Keywords

  • Anticonvulsant
  • Human α1-glucine receptor
  • Inhibitor
  • Phenyl alanine derivatives
  • Potentiator
  • Strychnine

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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