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

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Izvleček
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.

Jezik:Angleški jezik
Ključne besede:organoruthenium nitrophenanthroline complex, acetylcholinesterase, butyrylcholinesterase, glutathione S-transferase, mouse neuromuscular system, ruthenium, muscle relaxation, physiology, glutathione transferase
Vrsta gradiva:Članek v reviji (dk_c)
Tipologija:1.01 - Izvirni znanstveni članek
Organizacija:VF - Veterinarska fakulteta
BF - Biotehniška fakulteta
FKKT - Fakulteta za kemijo in kemijsko tehnologijo
Leto izida:2020
Status objave pri reviji:Objavljeno
Verzija članka:Založnikova različica članka
Št. strani:11 str.
Številčenje:Vol. 127, art. 110161
PID:20.500.12556/RUL-118028 Povezava se odpre v novem oknu
UDK:577.15:612.741
ISSN pri članku:1950-6007
DOI:10.1016/j.biopha.2020.110161 Povezava se odpre v novem oknu
COBISS.SI-ID:13704451 Povezava se odpre v novem oknu
Datum objave v RUL:14.08.2020
Število ogledov:495
Število prenosov:91
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
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Gradivo je del revije

Naslov:Biomedicine & pharmacotherapy
Založnik:Elsevier
ISSN:1950-6007
COBISS.SI-ID:23136261 Povezava se odpre v novem oknu

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Licenca:CC BY-NC-ND 4.0, Creative Commons Priznanje avtorstva-Nekomercialno-Brez predelav 4.0 Mednarodna
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