New safe method for preparation of sarin-exposed human erythrocytes acetylcholinesterase using non-toxic and stable sarin analogue isopropyl p-nitrophenyl methylphosphonate and its application to evaluation of nerve agent antidotes
A non-toxic and stable sarin analogue, isopropyl p-nitrophenyl methylphosphonate (INMP), was synthesized for safe preparation of sarin-exposed acetylcholinesterase (AChE). This agent was stable for years, able to be handled in an ordinary laboratory without special care, and its 50% inhibitory conce...
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| Veröffentlicht in: | Pharmaceutical research 2006-12, Vol.23 (12), p.2827-2833 |
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| creator | Ohta, Hikoto Ohmori, Takeshi Suzuki, Shinichi Ikegaya, Hiroshi Sakurada, Koichi Takatori, Takehiko |
| description | A non-toxic and stable sarin analogue, isopropyl p-nitrophenyl methylphosphonate (INMP), was synthesized for safe preparation of sarin-exposed acetylcholinesterase (AChE).
This agent was stable for years, able to be handled in an ordinary laboratory without special care, and its 50% inhibitory concentration (IC50) on 0.04 U/ml human erythrocytes AChE was 15 nM. This reagent was thought to be especially useful since it enables experiments that require sarin-inhibited AChE, such as the development of antidotes for sarin, in a usual laboratory. To demonstrate the usefulness of this method, 40 known and novel pyridinealdoxime methiodide (PAM)-type oxime antidotes were synthesized, and their reactivation activities to INMP-exposed AChE and structure-activities correlation were studied.
Among the antidotes tested in this experiment except for 2-PAM, the compound found to have the highest reactivation activity, was the novel hydrophobic 2-PAM-type compound, 2-[(hydroxyimino)methyl]-1-[4-(tert-butyl)benzyl] pyridinium bromide. |
| doi_str_mv | 10.1007/s11095-006-9123-1 |
| format | Article |
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This agent was stable for years, able to be handled in an ordinary laboratory without special care, and its 50% inhibitory concentration (IC50) on 0.04 U/ml human erythrocytes AChE was 15 nM. This reagent was thought to be especially useful since it enables experiments that require sarin-inhibited AChE, such as the development of antidotes for sarin, in a usual laboratory. To demonstrate the usefulness of this method, 40 known and novel pyridinealdoxime methiodide (PAM)-type oxime antidotes were synthesized, and their reactivation activities to INMP-exposed AChE and structure-activities correlation were studied.
Among the antidotes tested in this experiment except for 2-PAM, the compound found to have the highest reactivation activity, was the novel hydrophobic 2-PAM-type compound, 2-[(hydroxyimino)methyl]-1-[4-(tert-butyl)benzyl] pyridinium bromide.</description><identifier>ISSN: 0724-8741</identifier><identifier>EISSN: 1573-904X</identifier><identifier>DOI: 10.1007/s11095-006-9123-1</identifier><identifier>PMID: 17096183</identifier><language>eng</language><publisher>United States: Springer Nature B.V</publisher><subject>Acetylcholinesterase ; Acetylcholinesterase - blood ; Antidotes ; Antidotes - pharmacology ; Biological & chemical weapons ; Chemical Warfare Agents - pharmacology ; Cholinesterase Inhibitors - blood ; Cholinesterase Inhibitors - pharmacology ; Cholinesterase Reactivators - pharmacology ; Drug Evaluation, Preclinical ; Drug therapy ; Enzymes ; Erythrocytes ; Erythrocytes - drug effects ; Erythrocytes - enzymology ; Humans ; Hydrophobicity ; Indicators and Reagents ; Laboratories ; Magnetic Resonance Spectroscopy ; Nerve agents ; Pharmacology ; Pyridinium ; Sarin ; Sarin - analogs & derivatives ; Sarin - blood ; Sarin - pharmacology ; Spectrometry, Mass, Electrospray Ionization ; Structure-Activity Relationship ; Toxicology</subject><ispartof>Pharmaceutical research, 2006-12, Vol.23 (12), p.2827-2833</ispartof><rights>Springer Science+Business Media, LLC 2006</rights><rights>Springer Science+Business Media, Inc. 2006.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c385t-d731571121aa3b2a4a70444b3150bd99ed188828a01a401cf8bec30100ade37a3</citedby><cites>FETCH-LOGICAL-c385t-d731571121aa3b2a4a70444b3150bd99ed188828a01a401cf8bec30100ade37a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17096183$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ohta, Hikoto</creatorcontrib><creatorcontrib>Ohmori, Takeshi</creatorcontrib><creatorcontrib>Suzuki, Shinichi</creatorcontrib><creatorcontrib>Ikegaya, Hiroshi</creatorcontrib><creatorcontrib>Sakurada, Koichi</creatorcontrib><creatorcontrib>Takatori, Takehiko</creatorcontrib><title>New safe method for preparation of sarin-exposed human erythrocytes acetylcholinesterase using non-toxic and stable sarin analogue isopropyl p-nitrophenyl methylphosphonate and its application to evaluation of nerve agent antidotes</title><title>Pharmaceutical research</title><addtitle>Pharm Res</addtitle><description>A non-toxic and stable sarin analogue, isopropyl p-nitrophenyl methylphosphonate (INMP), was synthesized for safe preparation of sarin-exposed acetylcholinesterase (AChE).
This agent was stable for years, able to be handled in an ordinary laboratory without special care, and its 50% inhibitory concentration (IC50) on 0.04 U/ml human erythrocytes AChE was 15 nM. This reagent was thought to be especially useful since it enables experiments that require sarin-inhibited AChE, such as the development of antidotes for sarin, in a usual laboratory. To demonstrate the usefulness of this method, 40 known and novel pyridinealdoxime methiodide (PAM)-type oxime antidotes were synthesized, and their reactivation activities to INMP-exposed AChE and structure-activities correlation were studied.
Among the antidotes tested in this experiment except for 2-PAM, the compound found to have the highest reactivation activity, was the novel hydrophobic 2-PAM-type compound, 2-[(hydroxyimino)methyl]-1-[4-(tert-butyl)benzyl] pyridinium bromide.</description><subject>Acetylcholinesterase</subject><subject>Acetylcholinesterase - blood</subject><subject>Antidotes</subject><subject>Antidotes - pharmacology</subject><subject>Biological & chemical weapons</subject><subject>Chemical Warfare Agents - pharmacology</subject><subject>Cholinesterase Inhibitors - blood</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>Cholinesterase Reactivators - pharmacology</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drug therapy</subject><subject>Enzymes</subject><subject>Erythrocytes</subject><subject>Erythrocytes - drug effects</subject><subject>Erythrocytes - enzymology</subject><subject>Humans</subject><subject>Hydrophobicity</subject><subject>Indicators and Reagents</subject><subject>Laboratories</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Nerve agents</subject><subject>Pharmacology</subject><subject>Pyridinium</subject><subject>Sarin</subject><subject>Sarin - analogs & derivatives</subject><subject>Sarin - blood</subject><subject>Sarin - pharmacology</subject><subject>Spectrometry, Mass, Electrospray Ionization</subject><subject>Structure-Activity Relationship</subject><subject>Toxicology</subject><issn>0724-8741</issn><issn>1573-904X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kt-q1DAQxosonvXoA3gjQcG7aKbpbtNLOfgPDnqj4F2ZttNtDtmkJunx9Il9DWfdRUHwIiSZ_ObLZPIVxVNQr0Cp-nUCUM1WKrWTDZRawr1iA9tay0ZV3-4XG1WXlTR1BRfFo5RulFIGmuphcQG1anZg9Kb4-Yl-iIQjiQPlKQxiDFHMkWaMmG3wIox8HK2XdDeHRIOYlgN6QXHNUwz9mikJ7Cmvrp-Cs55SpoiJxJKs3wsfvMzhzvYC_SBSxs7RSZAD6MJ-IWFTmGOYVydm6W3m5USed8eKVjdPIfHwmOm3hs184Tw7258KzEHQLbrlT7me4i2je_KZE7IdAtf4uHgwokv05DxfFl_fvf1y9UFef37_8erNtey12WY51JobCFACou5KrLBWVVV1HFXd0DQ0gDGmNKgAKwX9aDrqteLfwIF0jfqyeHnS5Rd9X7gZ7cGmnpxDT2FJbanANDtdMvjiH_AmLJFbwsxuV5Vg-GuZev5fqmSO5Y4QnKA-hpQije0c7QHj2oJqj0ZpT0Zp2Sjt0SgtcM6zs_DSHWj4m3F2hv4Fuz-_yQ</recordid><startdate>200612</startdate><enddate>200612</enddate><creator>Ohta, Hikoto</creator><creator>Ohmori, Takeshi</creator><creator>Suzuki, Shinichi</creator><creator>Ikegaya, Hiroshi</creator><creator>Sakurada, Koichi</creator><creator>Takatori, Takehiko</creator><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7QO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>200612</creationdate><title>New safe method for preparation of sarin-exposed human erythrocytes acetylcholinesterase using non-toxic and stable sarin analogue isopropyl p-nitrophenyl methylphosphonate and its application to evaluation of nerve agent antidotes</title><author>Ohta, Hikoto ; Ohmori, Takeshi ; Suzuki, Shinichi ; Ikegaya, Hiroshi ; Sakurada, Koichi ; Takatori, Takehiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c385t-d731571121aa3b2a4a70444b3150bd99ed188828a01a401cf8bec30100ade37a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Acetylcholinesterase</topic><topic>Acetylcholinesterase - blood</topic><topic>Antidotes</topic><topic>Antidotes - pharmacology</topic><topic>Biological & chemical weapons</topic><topic>Chemical Warfare Agents - pharmacology</topic><topic>Cholinesterase Inhibitors - blood</topic><topic>Cholinesterase Inhibitors - pharmacology</topic><topic>Cholinesterase Reactivators - pharmacology</topic><topic>Drug Evaluation, Preclinical</topic><topic>Drug therapy</topic><topic>Enzymes</topic><topic>Erythrocytes</topic><topic>Erythrocytes - drug effects</topic><topic>Erythrocytes - enzymology</topic><topic>Humans</topic><topic>Hydrophobicity</topic><topic>Indicators and Reagents</topic><topic>Laboratories</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Nerve agents</topic><topic>Pharmacology</topic><topic>Pyridinium</topic><topic>Sarin</topic><topic>Sarin - analogs & derivatives</topic><topic>Sarin - blood</topic><topic>Sarin - pharmacology</topic><topic>Spectrometry, Mass, Electrospray Ionization</topic><topic>Structure-Activity Relationship</topic><topic>Toxicology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ohta, Hikoto</creatorcontrib><creatorcontrib>Ohmori, Takeshi</creatorcontrib><creatorcontrib>Suzuki, Shinichi</creatorcontrib><creatorcontrib>Ikegaya, Hiroshi</creatorcontrib><creatorcontrib>Sakurada, Koichi</creatorcontrib><creatorcontrib>Takatori, Takehiko</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Biotechnology Research Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Pharmaceutical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ohta, Hikoto</au><au>Ohmori, Takeshi</au><au>Suzuki, Shinichi</au><au>Ikegaya, Hiroshi</au><au>Sakurada, Koichi</au><au>Takatori, Takehiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>New safe method for preparation of sarin-exposed human erythrocytes acetylcholinesterase using non-toxic and stable sarin analogue isopropyl p-nitrophenyl methylphosphonate and its application to evaluation of nerve agent antidotes</atitle><jtitle>Pharmaceutical research</jtitle><addtitle>Pharm Res</addtitle><date>2006-12</date><risdate>2006</risdate><volume>23</volume><issue>12</issue><spage>2827</spage><epage>2833</epage><pages>2827-2833</pages><issn>0724-8741</issn><eissn>1573-904X</eissn><abstract>A non-toxic and stable sarin analogue, isopropyl p-nitrophenyl methylphosphonate (INMP), was synthesized for safe preparation of sarin-exposed acetylcholinesterase (AChE).
This agent was stable for years, able to be handled in an ordinary laboratory without special care, and its 50% inhibitory concentration (IC50) on 0.04 U/ml human erythrocytes AChE was 15 nM. This reagent was thought to be especially useful since it enables experiments that require sarin-inhibited AChE, such as the development of antidotes for sarin, in a usual laboratory. To demonstrate the usefulness of this method, 40 known and novel pyridinealdoxime methiodide (PAM)-type oxime antidotes were synthesized, and their reactivation activities to INMP-exposed AChE and structure-activities correlation were studied.
Among the antidotes tested in this experiment except for 2-PAM, the compound found to have the highest reactivation activity, was the novel hydrophobic 2-PAM-type compound, 2-[(hydroxyimino)methyl]-1-[4-(tert-butyl)benzyl] pyridinium bromide.</abstract><cop>United States</cop><pub>Springer Nature B.V</pub><pmid>17096183</pmid><doi>10.1007/s11095-006-9123-1</doi><tpages>7</tpages></addata></record> |
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| ispartof | Pharmaceutical research, 2006-12, Vol.23 (12), p.2827-2833 |
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| subjects | Acetylcholinesterase Acetylcholinesterase - blood Antidotes Antidotes - pharmacology Biological & chemical weapons Chemical Warfare Agents - pharmacology Cholinesterase Inhibitors - blood Cholinesterase Inhibitors - pharmacology Cholinesterase Reactivators - pharmacology Drug Evaluation, Preclinical Drug therapy Enzymes Erythrocytes Erythrocytes - drug effects Erythrocytes - enzymology Humans Hydrophobicity Indicators and Reagents Laboratories Magnetic Resonance Spectroscopy Nerve agents Pharmacology Pyridinium Sarin Sarin - analogs & derivatives Sarin - blood Sarin - pharmacology Spectrometry, Mass, Electrospray Ionization Structure-Activity Relationship Toxicology |
| title | New safe method for preparation of sarin-exposed human erythrocytes acetylcholinesterase using non-toxic and stable sarin analogue isopropyl p-nitrophenyl methylphosphonate and its application to evaluation of nerve agent antidotes |
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