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 (e6 p cymene)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 S transferase. 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 (IC50) of enzyme activity ranging from 16 to 26 mM. Moreover, C1 Cl inhibited the nerve evoked isometric muscle contraction (IC50 19.44 mM) without affecting the directly evoked muscle single twitch up to 40 mM. 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 mM) without any significant change in the resting membrane potential of muscle fibers up to 40 mM. Finally, C1 Cl (5 40 mM) decreased (i) the amplitude of miniature endplate potentials until a complete block by concentrations higher than 25 mM and (ii) their frequency at 10 mM 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.
Biomedicine pharmacotherapy Biomedecine pharmacotherapie