Structural and functional characterization of an organometallic ruthenium complex as a potential myorelaxant drug
ID Trobec, Tomaž (Author), ID Žužek, Monika C. (Author), ID Sepčić, Kristina (Author), ID Kladnik, Jerneja (Author), ID Kljun, Jakob (Author), ID Turel, Iztok (Author), ID Benoit, Evelyne (Author), ID Frangež, Robert (Author)

URLURL - Source URL, Visit https://www.sciencedirect.com/science/article/pii/S075333222030353X?via%3Dihub This link opens in a new window

In addition to antibacterial and antitumor effects, synthetic ruthenium complexes have been reported to inhibitseveral medicinally important enzymes, including acetylcholinesterase (AChE). They may also interact withmuscle-type nicotinic acetylcholine receptors (nAChRs) and thus affect the neuromuscular transmission andmuscle function. In the present study, the effects of the organometallic ruthenium complex of 5-nitro-1,10-phenanthroline (nitrophen) were evaluated on these systems. The organoruthenium-nitrophen complex [(η6-p-cymene)Ru(nitrophen)Cl]Cl; C22H21Cl2N3O2Ru (C1-Cl) was synthesized, structurally characterized and eval-uatedin vitrofor its inhibitory activity against electric eel acetylcholinesterase (eeAChE), human recombinantacetylcholinesterase (hrAChE), horse serum butyrylcholinesterase (hsBChE) and horse liver glutathione-S-transferase. The physiological effects of C1-Cl were then studied on isolated mouse phrenic nerve-hemi-diaphragm muscle preparations, by means of single twitch measurements and electrophysiological recordings.The compound C1-Cl acted as a competitive inhibitor of eeAChE, hrAChE and hsBChE with concentrationsproducing 50 % inhibition (IC50) of enzyme activity ranging from 16 to 26μM. Moreover, C1-Cl inhibited thenerve-evoked isometric muscle contraction (IC50= 19.44μM), without affecting the directly-evoked musclesingle twitch up to 40μM. The blocking effect of C1-Cl was rapid and almost completely reversed by neos-tigmine, a reversible cholinesterase inhibitor. The endplate potentials were also inhibited by C1-Cl in a con-centration-dependent manner (IC50= 7.6μM) without any significant change in the resting membrane potentialof musclefibers up to 40μM. Finally, C1-Cl (5–40μM) decreased (i) the amplitude of miniature endplatepotentials until a complete block by concentrations higher than 25μM and (ii) their frequency at 10μM or higherconcentrations. The compound C1-Cl reversibly blocked the neuromuscular transmissionin vitroby a non-de-polarizing mechanism and mainly through an action on postsynaptic nAChRs. The compound C1-Cl may betherefore interesting for further preclinical testing as a new competitive neuromuscular blocking, and thusmyorelaxant, drug

Keywords:Organoruthenium nitrophenanthroline complex, acetylcholinesterase, butyrylcholinesterase, glutathione S-transferase, mouse neuromuscular system
Work type:Article (dk_c)
Typology:1.01 - Original Scientific Article
Organization:VF - Veterinary Faculty
Publication status in journal:Published
Article version:Publisher's version of article
Number of pages:Str. 1-11
Numbering:Vol. 127, art. no. 110161
ISSN on article:1950-6007
DOI:10.1016/j.biopha.2020.110161 This link opens in a new window
COBISS.SI-ID:13704451 This link opens in a new window
Publication date in RUL:14.08.2020
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Record is a part of a journal

Title:Biomedicine & pharmacotherapy
COBISS.SI-ID:23136261 This link opens in a new window


License:CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Description:The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.
Licensing start date:14.08.2020

Document is financed by a project

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Name:Endokrini, imunski in encimski odzivi pri zdravih in bolnih živalih

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Name:Toksini in biomembrane

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Name:Napredna anorganska kemija

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