| Autor: |
Kulyk, V. B., Venhreniuk, A., Iegorova, O., Raevsky, A. V., Platonov, M. O., Maximyuk, O. |
| Předmět: |
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| Zdroj: |
Physiological Journal / Fiziologichnyi Zhurnal; 2022 Supplement, Vol. 68, p51-51, 2/3p |
| Abstrakt: |
All pharmacological analgesics known up to date have a variety of serious side effects limiting their use in medical practice. In this regard, the search for new pain relievers is an urgent problem in modern pharmacology. Microtubules of the cytoskeleton, which are capable of regulating the activity of ion channels involved in nociception processes, have recently been proposed as a promising target for such pharmacological agents. Our research is looking into the connection between the activity of enzymes that transform cytoskeleton proteins and the formation of a pain signal at the sensory terminals of primary nociceptive afferents. The role of voltage-gated sodium ion channels Nav1.7 type in the development and maintenance of chronic pain is well known: they provide rapid depolarization of the plasma membrane and are effectively blocked by tetrodotoxin (TTX). TTX-sensitive Nav1.7 highly expressed in the membranes of the dorsal root ganglia nociceptive neurons [1]. Following the identification of potential binding sites and the analysis of the results of virtual screening of chemical compounds, 43 compounds enzyme inhibitors involved in post-translational modifications of microtubule elements were synthesized. Proton nuclear magnetic resonance and chromatography-mass spectrometry were used to confirm the structure of the compounds. A model of the interaction of the ion channel and microtubules on the membrane's surface was created. [2]. As a result, this model was validated using the «patch-clamp» technique, which is the gold standard in the study of the pharmacology of cell membrane ion channels. The activity of synthesized compounds was tested at concentration of 100 µM on the native Nav1.7 channels expressed in 5-day cultured DRG neurons. According to the research results, the compounds Z116802612, Z12222865, Z26449000101, and Z2826002908 also have moderate inhibitory effect (25-50 %) on Nav1.7 at concentration of 100 µM and are the most active compounds in the studied series. Further research and possible structure optimization of these molecules will help to form a prototype of a new class of Nav1.7 channel activity modulators, which will help in development of novel type of non-opioid analgesic medications. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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