The use of bispyridinium non-oxime analogues for the restoration of nerve agent impaired neuromuscular transmission in rat hemidiaphragms – Structure optimization
Organophosphate pesticide poisoning challenges health care systems worldwide. Furthermore, nerve agents remain a continuous threat. The treatment options for organophosphate poisoning have virtually been unchanged for decades, relying on symptomatic treatment and the use of oximes to indirectly rest...
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| Published in: | Toxicology letters Vol. 397; pp. 42 - 47 |
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| Main Authors: | , , , , , |
| Format: | Journal Article |
| Language: | English |
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Elsevier B.V
01-06-2024
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| Abstract | Organophosphate pesticide poisoning challenges health care systems worldwide. Furthermore, nerve agents remain a continuous threat. The treatment options for organophosphate poisoning have virtually been unchanged for decades, relying on symptomatic treatment and the use of oximes to indirectly restore neuromuscular function. Hence, compounds targeting directly nicotinic acetylcholine receptors (nAChRs) might substantially improve treatment options. The current study investigated a series of bispyridinium analogues with a trimethylene or 2,2′-diethyloxy linker in a rat hemidiaphragm model, using indirect field stimulation. Methyl- and ethyl-substituted bispyridinium analogues restored neuromuscular function up to 37 ± 17% (MB419, a 3-methyl analogue) at a stimulation frequency of 20 Hz. The bispyridinium analogues with a 2- or 3-methyl group, or a 2- or 3-ethyl group, tended towards a higher restoration of neuromuscular function than those with a 4-methyl or 4-ethyl group, respectively. The current data can be used for future studies to optimize structure-based molecular modeling of compounds targeting the nAChR.
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•Bispyridinium non-oximes analogues with a trimethylene or 2,2′-diethyloxy linker and various substituents were studied.•Methyl- and ethyl- substituted compounds with a trimethylene linker were able to partially restore muscle force.•The investigated bispyridinium analogues can be used for future studies to optimize structure-based molecular modeling. |
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| AbstractList | Organophosphate pesticide poisoning challenges health care systems worldwide. Furthermore, nerve agents remain a continuous threat. The treatment options for organophosphate poisoning have virtually been unchanged for decades, relying on symptomatic treatment and the use of oximes to indirectly restore neuromuscular function. Hence, compounds targeting directly nicotinic acetylcholine receptors (nAChRs) might substantially improve treatment options. The current study investigated a series of bispyridinium analogues with a trimethylene or 2,2'-diethyloxy linker in a rat hemidiaphragm model, using indirect field stimulation. Methyl- and ethyl-substituted bispyridinium analogues restored neuromuscular function up to 37 ± 17% (MB419, a 3-methyl analogue) at a stimulation frequency of 20 Hz. The bispyridinium analogues with a 2- or 3-methyl group, or a 2- or 3-ethyl group, tended towards a higher restoration of neuromuscular function than those with a 4-methyl or 4-ethyl group, respectively. The current data can be used for future studies to optimize structure-based molecular modeling of compounds targeting the nAChR. Organophosphate pesticide poisoning challenges health care systems worldwide. Furthermore, nerve agents remain a continuous threat. The treatment options for organophosphate poisoning have virtually been unchanged for decades, relying on symptomatic treatment and the use of oximes to indirectly restore neuromuscular function. Hence, compounds targeting directly nicotinic acetylcholine receptors (nAChRs) might substantially improve treatment options. The current study investigated a series of bispyridinium analogues with a trimethylene or 2,2'-diethyloxy linker in a rat hemidiaphragm model, using indirect field stimulation. Methyl- and ethyl-substituted bispyridinium analogues restored neuromuscular function up to 37 ± 17% (MB419, a 3-methyl analogue) at a stimulation frequency of 20 Hz. The bispyridinium analogues with a 2- or 3-methyl group, or a 2- or 3-ethyl group, tended towards a higher restoration of neuromuscular function than those with a 4-methyl or 4-ethyl group, respectively. The current data can be used for future studies to optimize structure-based molecular modeling of compounds targeting the nAChR.Organophosphate pesticide poisoning challenges health care systems worldwide. Furthermore, nerve agents remain a continuous threat. The treatment options for organophosphate poisoning have virtually been unchanged for decades, relying on symptomatic treatment and the use of oximes to indirectly restore neuromuscular function. Hence, compounds targeting directly nicotinic acetylcholine receptors (nAChRs) might substantially improve treatment options. The current study investigated a series of bispyridinium analogues with a trimethylene or 2,2'-diethyloxy linker in a rat hemidiaphragm model, using indirect field stimulation. Methyl- and ethyl-substituted bispyridinium analogues restored neuromuscular function up to 37 ± 17% (MB419, a 3-methyl analogue) at a stimulation frequency of 20 Hz. The bispyridinium analogues with a 2- or 3-methyl group, or a 2- or 3-ethyl group, tended towards a higher restoration of neuromuscular function than those with a 4-methyl or 4-ethyl group, respectively. The current data can be used for future studies to optimize structure-based molecular modeling of compounds targeting the nAChR. Organophosphate pesticide poisoning challenges health care systems worldwide. Furthermore, nerve agents remain a continuous threat. The treatment options for organophosphate poisoning have virtually been unchanged for decades, relying on symptomatic treatment and the use of oximes to indirectly restore neuromuscular function. Hence, compounds targeting directly nicotinic acetylcholine receptors (nAChRs) might substantially improve treatment options. The current study investigated a series of bispyridinium analogues with a trimethylene or 2,2′-diethyloxy linker in a rat hemidiaphragm model, using indirect field stimulation. Methyl- and ethyl-substituted bispyridinium analogues restored neuromuscular function up to 37 ± 17% (MB419, a 3-methyl analogue) at a stimulation frequency of 20 Hz. The bispyridinium analogues with a 2- or 3-methyl group, or a 2- or 3-ethyl group, tended towards a higher restoration of neuromuscular function than those with a 4-methyl or 4-ethyl group, respectively. The current data can be used for future studies to optimize structure-based molecular modeling of compounds targeting the nAChR. [Display omitted] •Bispyridinium non-oximes analogues with a trimethylene or 2,2′-diethyloxy linker and various substituents were studied.•Methyl- and ethyl- substituted compounds with a trimethylene linker were able to partially restore muscle force.•The investigated bispyridinium analogues can be used for future studies to optimize structure-based molecular modeling. |
| Author | Amend, Niko Bird, Mike Worek, Franz Green, A.Christopher Timperley, Christopher M. Seeger, Thomas |
| Author_xml | – sequence: 1 givenname: Niko surname: Amend fullname: Amend, Niko email: nikoamend@bundeswehr.org organization: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, Munich 80937, Germany – sequence: 2 givenname: Christopher M. surname: Timperley fullname: Timperley, Christopher M. organization: Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK – sequence: 3 givenname: Mike surname: Bird fullname: Bird, Mike organization: Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK – sequence: 4 givenname: A.Christopher surname: Green fullname: Green, A.Christopher organization: Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK – sequence: 5 givenname: Franz surname: Worek fullname: Worek, Franz organization: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, Munich 80937, Germany – sequence: 6 givenname: Thomas surname: Seeger fullname: Seeger, Thomas organization: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, Munich 80937, Germany |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/38723915$$D View this record in MEDLINE/PubMed |
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| Copyright | 2024 Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved. |
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| Keywords | Bispyridinium non-oximes Organophosphate Acetylcholinesterase Nerve agent Nicotinic receptor |
| Language | English |
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