期刊
BIOMEDICINE & PHARMACOTHERAPY
卷 127, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2020.110161
关键词
Organoruthenium nitrophenanthroline complex; Acetylcholinesterase; Butyrylcholinesterase; Glutathione S-transferase; Mouse neuromuscular system
资金
- Slovenian research grants [P4-0053, P10207, P1-0175]
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 [(eta(6)-p-cyrnene)Ru(nitrophen)Cl]Cl; C22H21Cl2N3O2Ru (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-C1 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 (IC50) of enzyme activity ranging from 16 to 26 mu M. Moreover, C1-Cl inhibited the nerve-evoked isometric muscle contraction (IC50 = 19.44 mu M), without affecting the directly-evoked muscle single twitch up to 40 mu M. 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 (IC50 = 7.6 mu M) without any significant change in the resting membrane potential of muscle fibers up to 40 mu M. Finally, C1-Cl (5-40 mu M) decreased (i) the amplitude of miniature endplate potentials until a complete block by concentrations higher than 25 mu M and (ii) their frequency at 10 mu M 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.
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