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)

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In addition to antibacterial and antitumor effects, synthetic ruthenium complexes have been reported to inhibit several medicinally important enzymes, including acetylcholinesterase (AChE). They may also interact with muscle-type nicotinic acetylcholine receptors (nAChRs) and thus affect the neuromuscular transmission and muscle 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 [(η$^6$-pcymene)Ru(nitrophen)Cl]Cl; C$_{22}$H$_{21}$Cl$_2$N$_3$O$_2$Ru (C1-Cl) was synthesized, structurally characterized and evaluated in vitro for its inhibitory activity against electric eel acetylcholinesterase (eeAChE), human recombinant acetylcholinesterase (hrAChE), horse serum butyrylcholinesterase (hsBChE) and horse liver glutathione-Stransferase. The physiological effects of C1-Cl were then studied on isolated mouse phrenic nerve-hemidiaphragm 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 concentrations producing 50 % inhibition (IC$_{50}$) of enzyme activity ranging from 16 to 26 μM. Moreover, C1-Cl inhibited the nerve-evoked isometric muscle contraction (IC$_{50}$ = 19.44 μM), without affecting the directly-evoked muscle single twitch up to 40 μM. The blocking effect of C1-Cl was rapid and almost completely reversed by neostigmine, a reversible cholinesterase inhibitor. The endplate potentials were also inhibited by C1-Cl in a concentration-dependent manner (IC$_{50}$ = 7.6 μM) without any significant change in the resting membrane potential of muscle fibers up to 40 μM. Finally, C1-Cl (5–40 μM) decreased (i) the amplitude of miniature endplate potentials until a complete block by concentrations higher than 25 μM and (ii) their frequency at 10 μM or higher concentrations. The compound C1-Cl reversibly blocked the neuromuscular transmission in vitro by a non-depolarizing mechanism and mainly through an action on postsynaptic nAChRs. The compound C1-Cl may be therefore interesting for further preclinical testing as a new competitive neuromuscular blocking, and thus myorelaxant, drug.

Keywords:organoruthenium nitrophenanthroline complex, acetylcholinesterase, butyrylcholinesterase, glutathione S-transferase, mouse neuromuscular system, ruthenium, muscle relaxation, physiology, glutathione transferase
Work type:Article
Typology:1.01 - Original Scientific Article
Organization:VF - Veterinary Faculty
BF - Biotechnical Faculty
FKKT - Faculty of Chemistry and Chemical Technology
Publication status:Published
Publication version:Version of Record
Number of pages:11 str.
Numbering:Vol. 127, art. 110161
PID:20.500.12556/RUL-118028 This link opens in a new window
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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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.


Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:P4-0053
Name:Endokrini, imunski in encimski odzivi pri zdravih in bolnih živalih

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:P1-0207
Name:Toksini in biomembrane

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:P1-0175
Name:Napredna anorganska kemija

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Funding programme:Young researchers

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