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Novel organoruthenium(II) complex C1 selectively inhibits butyrylcholinesterase without side effects on neuromuscular transmission
ID
Trobec, Tomaž
(
Author
),
ID
Žužek, Monika C.
(
Author
),
ID
Sepčić, Kristina
(
Author
),
ID
Kladnik, Jerneja
(
Author
),
ID
Turel, Iztok
(
Author
),
ID
Frangež, Robert
(
Author
)
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https://www.mdpi.com/1422-0067/24/3/2681
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Abstract
Enzyme butyrylcholinesterase (BChE) shows increased activity in some brain regions after progression of Alzheimer’s disease and is therefore one of the therapeutic targets for symptomatic treatment of this neurodegenerative disorder. The organoruthenium(II) complex [(η$^6$-p-cymene)Ru(II)(1-hydroxy-3-methoxypyridine-2(1H)-thionato)pta]PF$_6$ (C1) was designed based on the results of our previous structure–activity studies. Inhibitory activity toward cholinesterase enzymes shows that this complex selectively, competitively, and reversibly inhibits horse serum BChE (hsBChE) with an IC$_{50}$ value of 2.88 µM. When tested at supra-pharmacological concentrations (30, 60, 90, and 120 µM), C1 had no significant effect on the maximal amplitude of nerve-evoked and directly elicited single-twitch and tetanic contractions. At the highest tested concentration (120 µM), C1 had no effect on resting membrane potential, but significantly decreased the amplitude of miniature end-plate potentials (MEPP) without reducing their frequency. The same concentration of C1 had no effect on the amplitude of end-plate potentials (EPP), however it shortened the half-decay time of MEPPs and EPPs. The decrease in the amplitude of MEPPs and shortening of the half-decay time of MEPPs and EPPs suggest a possible weak inhibitory effect on muscle-type nicotinic acetylcholine receptors (nAChR). These combined results show that, when applied at supra-pharmacological concentrations up to 120 µM, C1 does not importantly affect the physiology of neuromuscular transmission and skeletal muscle contraction.
Language:
English
Keywords:
organoruthenium(II) complex
,
acetylcholinesterase
,
butyrylcholinesterase
,
mouse neuromuscular system
,
ruthenium
,
Alzheimer disease
,
neurodegenerative diseases
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
Year:
2023
Number of pages:
14 str.
Numbering:
Vol. 24, iss. 3, art. 2681
PID:
20.500.12556/RUL-144178
UDC:
616-092
ISSN on article:
1422-0067
DOI:
10.3390/ijms24032681
COBISS.SI-ID:
140487427
Publication date in RUL:
02.02.2023
Views:
999
Downloads:
100
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Record is a part of a journal
Title:
International journal of molecular sciences
Shortened title:
Int. j. mol. sci.
Publisher:
MDPI
ISSN:
1422-0067
COBISS.SI-ID:
2779162
Licences
License:
CC BY 4.0, Creative Commons Attribution 4.0 International
Link:
http://creativecommons.org/licenses/by/4.0/
Description:
This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Projects
Funder:
ARRS - Slovenian Research Agency
Project number:
P4-0053
Name:
Endokrini, imunski in encimski odzivi pri zdravih in bolnih živalih
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0207
Name:
Toksini in biomembrane
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0175
Name:
Napredna anorganska kemija
Funder:
ARRS - Slovenian Research Agency
Funding programme:
Young researchers
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