20.500.12556/RUL-118028 Structural and functional characterization of an organometallic ruthenium complex as a potential myorelaxant drug 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. organoruthenium nitrophenanthroline complex acetylcholinesterase butyrylcholinesterase glutathione S-transferase mouse neuromuscular system ruthenium muscle relaxation physiology glutathione transferase true false true Angleški jezik Ni določen Članek v reviji 2020-08-14 09:54:04 2020-08-14 09:54:04 2022-08-30 04:01:07 0000-00-00 00:00:00 2020 0 0 11 str. art. 110161 Vol. 127 2020 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577.15:612.741 1950-6007 10.1016/j.biopha.2020.110161 13704451 23136261 1-s2.0-S075333222030353X-main.pdf 1-s2.0-S075333222030353X-main.pdf 1 C1AFD3650278B4A23FF080BD5DF317A4 af9d60507c1982f349720fb8a3a011952dfb3f086da4272d3f1e2b5110a0831a 21536060-fc33-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=157991 https://www.sciencedirect.com/science/article/pii/S075333222030353X 0 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=131961 Veterinarska fakulteta Biotehniška fakulteta Fakulteta za kemijo in kemijsko tehnologijo 0 0 0