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Central Nervous System Agents in Medicinal Chemistry

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ISSN (Print): 1871-5249
ISSN (Online): 1875-6166

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Research Article

Effect of Organic Solvents on Acetylcholinesterase Inhibition and Enzyme Kinetics

Author(s): Dnyaneshwar Baswar and Awanish Mishra*

Volume 23, Issue 1, 2023

Published on: 15 May, 2023

Page: [40 - 47] Pages: 8

DOI: 10.2174/1871524923666230417094549

Price: $65

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Abstract

Background: The most widespread signalling system in the brain is the cholinergic system, which plays a central role in the progress of Alzheimer’s diseases (AD). Current AD treatment primarily targets the neuronal acetylcholinesterase (AChE) enzyme. The finding of AChE activity may play a vital role in optimizing assays for drug discovery of new AChE inhibiting agents. During in-vitro assay of AChE activity, the use of various organic solvents is imperative.

Objective: The present study is designed to evaluate the effect of different organic solvents on enzyme activity and enzyme kinetics.

Method: Organic solvents' AChE inhibitory potential (including enzyme kinetics: Vmax, Km and Kcat) was evaluated using substrate velocity curve by using non-linear reversion Michaelis-Menten kinetic function.

Results: DMSO was found to have the most potent AChE inhibitory effect, followed by acetonitrile and ethanol. The kinetic study revealed DMSO as a mixed inhibitory effect (competitive/noncompetitive manner), ethanol as non-competitive, and acetonitrile as a competitive inhibitor of the AChE enzyme. Methanol has shown a negligible impact on enzyme inhibition and kinetics, suggesting its suitability for the AChE assay.

Conclusion: We assume that our study results will help design the experimental protocols and support analyzing investigational outcomes while screening and biological evaluation of new molecules using methanol as solvent/cosolvent.

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[1]
Ferreira-Vieira, T.H.; Guimaraes, I.M.; Silva, F.R.; Ribeiro, F.M. Alzheimer’s disease: Targeting the cholinergic system. Curr. Neuropharmacol., 2016, 14(1), 101-115.
[http://dx.doi.org/10.2174/1570159X13666150716165726] [PMID: 26813123]
[2]
Pietsch, M.; Christian, L.; Inhester, T.; Petzold, S.; Gütschow, M. Kinetics of inhibition of acetylcholinesterase in the presence of acetonitrile. FEBS J., 2009, 276(8), 2292-2307.
[http://dx.doi.org/10.1111/j.1742-4658.2009.06957.x] [PMID: 19292865]
[3]
Cavdar, H.; Senturk, M.; Guney, M.; Durdagi, S.; Kayik, G.; Supuran, C.T.; Ekinci, D. Inhibition of acetylcholinesterase and butyrylcholinesterase with uracil derivatives: Kinetic and computational studies. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 429-437.
[http://dx.doi.org/10.1080/14756366.2018.1543288] [PMID: 30734597]
[4]
Obregon, A.D.C.; Schetinger, M.R.C.; Correa, M.M.; Morsch, V.M.; Silva, J.E.P.; Martins, M.A.P.; Bonacorso, H.G.; Zanatta, N. Effects per se of organic solvents in the cerebral acetylcholinesterase of rats. Neurochem. Res., 2005, 30(3), 379-384.
[http://dx.doi.org/10.1007/s11064-005-2612-5] [PMID: 16018582]
[5]
Hampel, H.; Mesulam, M.M.; Cuello, A.C.; Farlow, M.R.; Giacobini, E.; Grossberg, G.T.; Khachaturian, A.S.; Vergallo, A.; Cavedo, E.; Snyder, P.J.; Khachaturian, Z.S. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain, 2018, 141(7), 1917-1933.
[http://dx.doi.org/10.1093/brain/awy132] [PMID: 29850777]
[6]
Nikl, K.; Castillo, S.; Hoie, E.; O’Brien, K.K. Alzheimer’s disease: Current treatments and potential new agents. US Pharm., 2019, 44, 20-23.
[7]
Zheng, W.; Thorne, N.; McKew, J.C. Phenotypic screens as a renewed approach for drug discovery. Drug Discov. Today, 2013, 18(21-22), 1067-1073.
[http://dx.doi.org/10.1016/j.drudis.2013.07.001] [PMID: 23850704]
[8]
Kumar, A.; Darreh-Shori, T. DMSO: A mixed-competitive inhibitor of human acetylcholinesterase. ACS Chem. Neurosci., 2017, 8(12), 2618-2625.
[http://dx.doi.org/10.1021/acschemneuro.7b00344] [PMID: 29017007]
[9]
Di, L.; Kerns, E.H. Biological assay challenges from compound solubility: Strategies for bioassay optimization. Drug Discov. Today, 2006, 11(9-10), 446-451.
[http://dx.doi.org/10.1016/j.drudis.2006.03.004] [PMID: 16635808]
[10]
Ellman, G.L.; Courtney, K.D.; Andres, V., Jr; Featherstone, R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol., 1961, 7(2), 88-95.
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]
[11]
Mandal, M.; Jaiswal, P.; Mishra, A. Curcumin loaded nanoparticles reversed monocrotophos induced motor impairment and memory deficit: Role of oxidative stress and intracellular calcium level. J. Drug Deliv. Sci. Technol., 2020, 56, 101559.
[http://dx.doi.org/10.1016/j.jddst.2020.101559]
[12]
Mandal, M.; Jaiswal, P.; Mishra, A. Role of curcumin and its nanoformulations in neurotherapeutics: A comprehensive review. J. Biochem. Mol. Toxicol., 2020, 34(6), e22478.
[http://dx.doi.org/10.1002/jbt.22478] [PMID: 32124518]
[13]
Karumuri, S.B.; Singh, H.; Naqvi, S.; Mishra, A.; Flora, S.J.S. Impact of chronic low dose exposure of monocrotophos in rat brain: Oxidative/nitrosative stress, neuronal changes and cholinesterase activity. Toxicol. Rep., 2019, 6, 1295-1303.
[http://dx.doi.org/10.1016/j.toxrep.2019.11.005] [PMID: 31867220]
[14]
Mishra, C.B.; Kumari, S.; Manral, A.; Prakash, A.; Saini, V.; Lynn, A.M.; Tiwari, M. Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2017, 125, 736-750.
[http://dx.doi.org/10.1016/j.ejmech.2016.09.057] [PMID: 27721157]
[15]
Caylak, E.; Aytekin, M.; Halifeoglu, I. Antioxidant effects of methionine, α-lipoic acid, N-acetylcysteine and homocysteine on lead-induced oxidative stress to erythrocytes in rats. Exp. Toxicol. Pathol., 2008, 60(4-5), 289-294.
[http://dx.doi.org/10.1016/j.etp.2007.11.004] [PMID: 18407480]
[16]
Tracey, K.J.; Czura, C.J.; Ivanova, S. Mind over immunity. FASEB J., 2001, 15(9), 1575-1576.
[http://dx.doi.org/10.1096/fj.01-0148hyp] [PMID: 11427490]
[17]
Cheng, K.; Samimi, R.; Xie, G.; Shant, J.; Drachenberg, C.; Wade, M.; Davis, R.J.; Nomikos, G.; Raufman, J.P. Acetylcholine release by human colon cancer cells mediates autocrine stimulation of cell proliferation. Am. J. Physiol. Gastrointest. Liver Physiol., 2008, 295(3), G591-G597.
[http://dx.doi.org/10.1152/ajpgi.00055.2008] [PMID: 18653726]
[18]
Kryger, G.; Silman, I.; Sussman, J.L. Structure of acetylcholinesterase complexed with E2020 (Aricept®): Implications for the design of new anti-Alzheimer drugs. Structure, 1999, 7(3), 297-307.
[http://dx.doi.org/10.1016/S0969-2126(99)80040-9] [PMID: 10368299]
[19]
Bell, G.; Janssen, A.E.M.; Halling, P.J. Water activity fails to predict critical hydration level for enzyme activity in polar organic solvents: Interconversion of water concentrations and activities. Enzyme Microb. Technol., 1997, 20(6), 471-477.
[http://dx.doi.org/10.1016/S0141-0229(96)00204-9]
[20]
Tabakoff, B.; Hoffman, P.L.; Liljequist, S. Effects of ethanol on the activity of brain enzymes. Enzyme, 1987, 37(1-2), 70-86.
[http://dx.doi.org/10.1159/000469242] [PMID: 3032606]
[21]
Sook, S.; Portia, W.; Chang-Hwei, C. Biochemical studies of the actions of ethanol on acetylcholinesterase activity: Ethnol-enzyme-solvent interaction. Int. J. Biochem., 1991, 23(2), 169-174.
[http://dx.doi.org/10.1016/0020-711X(91)90185-P] [PMID: 1999262]
[22]
Franks, F.; Ives, D.J.G. The structural properties of alcohol–water mixtures. Q. Rev. Chem. Soc., 1966, 20(1), 1-44.
[http://dx.doi.org/10.1039/QR9662000001]
[23]
Ramsay, R.; Tipton, K. Assessment of enzyme inhibition: A review with examples from the development of monoamine oxidase and cholinesterase inhibitory drugs. Molecules, 2017, 22(7), 1192.
[http://dx.doi.org/10.3390/molecules22071192] [PMID: 28714881]

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