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      Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

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          Abstract

          Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE ( hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE ( EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring.

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          Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase.

          C Hirth, L. Sabatier, Israel Silman … (1993)
          Binding sites of Torpedo acetylcholinesterase (EC 3.1.1.7) for quaternary ligands were investigated by x-ray crystallography and photoaffinity labeling. Crystal structures of complexes with ligands were determined at 2.8-A resolution. In a complex with edrophonium, and quaternary nitrogen of the ligand interacts with the indole of Trp-84, and its m-hydroxyl displays bifurcated hydrogen bonding to two members of the catalytic triad, Ser-200 and His-440. In a complex with tacrine, the acridine is stacked against the indole of Trp-84. The bisquaternary ligand decamethonium is oriented along the narrow gorge leading to the active site; one quaternary group is apposed to the indole of Trp-84 and the other to that of Trp-279, near the top of the gorge. The only major conformational difference between the three complexes is in the orientation of the phenyl ring of Phe-330. In the decamethonium complex it lies parallel to the surface of the gorge; in the other two complexes it is positioned to make contact with the bound ligand. This close interaction was confirmed by photoaffinity labelling by the photosensitive probe 3H-labeled p-(N,N-dimethylamino)benzenediazonium fluoroborate, which labeled, predominantly, Phe-330 within the active site. Labeling of Trp-279 was also observed. One mole of label is incorporated per mole of AcChoEase inactivated, indicating that labeling of Trp-279 and that of Phe-330 are mutually exclusive. The structural and chemical data, together, show the important role of aromatic groups as binding sites for quaternary ligands, and they provide complementary evidence assigning Trp-84 and Phe-330 to the "anionic" subsite of the active site and Trp-279 to the "peripheral" anionic site.
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            Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease.

            Irene Bolea, F. Luque, Mourad Chioua … (2012)
            A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50=5.2±1.1 nM) and MAO-B (IC50=43±8.0 nM) and is a moderately potent inhibitor of AChE (IC50=0.35±0.01 μM) and BuChE (IC50=0.46±0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.
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              Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment.

              Jiří Bajgar (2003)
              OP/nerve agents are still considered as important chemicals acting on living organisms and are widely used. They are characterized according to their action as compounds influencing cholinergic nerve transmission via inhibition of AChE. Modeling of this action and extrapolation of experimental data from animals to humans is more possible for highly toxic agents than for the OP. The symptoms of intoxication comprise nicotinic, muscarinic, and central symptoms; for some OP/nerve agents, a delayed neurotoxicity is observed. Cholinesterases (AChE and BuChE) are characterized as the main enzymes involved in the toxic effect of these compounds, including molecular forms. The activity of both enzymes (and molecular forms) is influenced by inhibitors (reversible, irreversible, and allosteric) and other factors, such as pathological states. There are different methods for cholinesterase determination; however, the most frequent is the method based on the hydrolysis of thiocholine esters and subsequent detection of free SH-group of the released thiocholine. The diagnosis of OP/nerve agent poisoning is based on anamnesis, the clinical status of the intoxicated organism, and on cholinesterase determination in the blood. For nerve agent intoxication, AChE in the red blood cell is more diagnostically important than BuChE activity in the plasma. This enzyme is a good diagnostic marker for intoxication with OP pesticides. Some other biochemical examinations are recommended, especially arterial blood gas, blood pH, minerals, and some other specialized parameters usually not available in all clinical laboratories. These special examinations are important for prognosis of the intoxication, for effective treatment, and for retrospective analysis of the agent used for exposure. Some principles of prophylaxis against OP/nerve agent poisoning comprising the administration of reversible cholinesterase inhibitors such as pyridostigmine (alone or in combination with other drugs), scavengers such as preparations of cholinesterases, some therapeutic drugs, and possible combinations are given. Basic principles of the treatment of nerve agent OP poisoning are described. They are based on the administration of anticholinergics (mostly atropine but some other anticholinergics can be recommended) as a symptomatic treatment, cholinesterase reactivators as a causal treatment (different types but without a universal reactivator against all OP/nerve agents) as the first aid and medical treatment, and anticonvulsants, preferably diazepam though some other effective benzodiazepines are available. New drugs for the treatment are under experimental study based on new approaches to the mechanism of action. Future trends in the complex research of these compounds, which is important not only for the treatment of intoxication but also for the quantitative and qualitative increase of our knowledge of toxicology, neurochemistry, neuropharmacology, clinical biochemistry, and analytical chemistry in general, are characterized.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: Molecular Diversity Preservation International (MDPI)
                ISSN (Electronic): 1422-0067
                Publication date Collection: August 2013
                Publication date (Electronic): 16 August 2013
                Volume: 14
                Issue: 8
                Pages: 16882-16900
                Affiliations
                [1 ]Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; E-Mails: sepsova@ 123456pmfhk.cz (V.S.); korabecny@ 123456pmfhk.cz (J.K.); zemek.filip@ 123456gmail.com (F.Z.)
                [2 ]Department of Public Health, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; E-Mail: karasova@ 123456pmfhk.cz
                [3 ]University Hospital, Biomedicinal Research Centre, Sokolska 581, 50005 Hradec Kralove, Czech Republic; E-Mail: rafael.dolezal@ 123456fnhk.cz
                [4 ]Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Ave, Livermore, CA 94550, USA; E-Mail: Bennion1@ 123456llnl.gov
                [5 ]Center of Advances Studies, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ]Author to whom correspondence should be addressed; E-Mail: kamil.kuca@ 123456fnhk.cz ; Tel.: +420-495-832-923; Fax: +420-495-518-094.
                Article
                Publisher ID: ijms-14-16882
                DOI: 10.3390/ijms140816882
                PMC ID: 3759941
                PubMed ID: 23959117
                SO-VID: b6fe5287-cab4-409e-80e9-fe4f544d78d1
                Copyright © © 2013 by the authors; licensee MDPI, Basel, Switzerland
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 08 May 2013
                Date revision received : 01 August 2013
                Date accepted : 02 August 2013
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: oximes,acetylcholinesterase,inhibitors,sar study
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: oximes, acetylcholinesterase, inhibitors, sar study

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