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Chlorine substituents and linker topology as factors of 5-HT 6 R activity for novel highly active 1,3,5-triazine derivatives with procognitive properties in vivo
In the light of recent lines of evidence, 5-HT R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied...
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| Published in: | European journal of medicinal chemistry 2020-10, Vol.203, p.112529 |
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| container_title | European journal of medicinal chemistry |
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| creator | Sudoł, Sylwia Kucwaj-Brysz, Katarzyna Kurczab, Rafał Wilczyńska, Natalia Jastrzębska-Więsek, Magdalena Satała, Grzegorz Latacz, Gniewomir Głuch-Lutwin, Monika Mordyl, Barbara Żesławska, Ewa Nitek, Wojciech Partyka, Anna Buzun, Kamila Doroz-Płonka, Agata Wesołowska, Anna Bielawska, Anna Handzlik, Jadwiga |
| description | In the light of recent lines of evidence, 5-HT
R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT
R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HT
R ligands. The new compounds were rationally designed as modifications of lead, 4-(1-(2-chlorophenoxy)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (1), involving an introduction of: (i) two chlorines at benzene ring and (ii) varied linkers joining the triazine ring to aromatic ethers. Synthesis, in vitro and in vivo biological tests and computer-aided SAR analysis for 19 new compounds were carried out. Most of the new triazines displayed high affinity (K
|
| format | article |
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R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT
R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HT
R ligands. The new compounds were rationally designed as modifications of lead, 4-(1-(2-chlorophenoxy)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (1), involving an introduction of: (i) two chlorines at benzene ring and (ii) varied linkers joining the triazine ring to aromatic ethers. Synthesis, in vitro and in vivo biological tests and computer-aided SAR analysis for 19 new compounds were carried out. Most of the new triazines displayed high affinity (K
< 100 nM) and selectivity towards 5-HT
R, with respect to 5-HT
R, 5-HT
R and D
R. The crystallography-supported docking studies, including quantum-polarized ligand docking (QPLD), indicated that chlorine atoms may be involved in different type of halogen bonding, however, the linker properties seem to predominately affect the 5-HT
R affinity. 4-[1-(2,5-Dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (9), which displayed: the highest affinity (K
= 6 nM), very strong 5-HT
R antagonistic action (K
= 27 pM), procognitive effects in vivo in novel object recognition (NOR) test in rats, a very good permeability in PAMPA model and satisfying safety in vitro, was identified as the most potent 1,3,5-triazine agent so far, useful as a new lead for further research.</description><identifier>EISSN: 1768-3254</identifier><identifier>PMID: 32693296</identifier><language>eng</language><publisher>France</publisher><subject>Animals ; Chlorine - chemistry ; Cognition - drug effects ; Molecular Docking Simulation ; Protein Conformation ; Rats ; Receptors, Serotonin - chemistry ; Receptors, Serotonin - metabolism ; Safety ; Structure-Activity Relationship ; Triazines - chemistry ; Triazines - metabolism ; Triazines - pharmacology</subject><ispartof>European journal of medicinal chemistry, 2020-10, Vol.203, p.112529</ispartof><rights>Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32693296$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sudoł, Sylwia</creatorcontrib><creatorcontrib>Kucwaj-Brysz, Katarzyna</creatorcontrib><creatorcontrib>Kurczab, Rafał</creatorcontrib><creatorcontrib>Wilczyńska, Natalia</creatorcontrib><creatorcontrib>Jastrzębska-Więsek, Magdalena</creatorcontrib><creatorcontrib>Satała, Grzegorz</creatorcontrib><creatorcontrib>Latacz, Gniewomir</creatorcontrib><creatorcontrib>Głuch-Lutwin, Monika</creatorcontrib><creatorcontrib>Mordyl, Barbara</creatorcontrib><creatorcontrib>Żesławska, Ewa</creatorcontrib><creatorcontrib>Nitek, Wojciech</creatorcontrib><creatorcontrib>Partyka, Anna</creatorcontrib><creatorcontrib>Buzun, Kamila</creatorcontrib><creatorcontrib>Doroz-Płonka, Agata</creatorcontrib><creatorcontrib>Wesołowska, Anna</creatorcontrib><creatorcontrib>Bielawska, Anna</creatorcontrib><creatorcontrib>Handzlik, Jadwiga</creatorcontrib><title>Chlorine substituents and linker topology as factors of 5-HT 6 R activity for novel highly active 1,3,5-triazine derivatives with procognitive properties in vivo</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>In the light of recent lines of evidence, 5-HT
R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT
R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HT
R ligands. The new compounds were rationally designed as modifications of lead, 4-(1-(2-chlorophenoxy)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (1), involving an introduction of: (i) two chlorines at benzene ring and (ii) varied linkers joining the triazine ring to aromatic ethers. Synthesis, in vitro and in vivo biological tests and computer-aided SAR analysis for 19 new compounds were carried out. Most of the new triazines displayed high affinity (K
< 100 nM) and selectivity towards 5-HT
R, with respect to 5-HT
R, 5-HT
R and D
R. The crystallography-supported docking studies, including quantum-polarized ligand docking (QPLD), indicated that chlorine atoms may be involved in different type of halogen bonding, however, the linker properties seem to predominately affect the 5-HT
R affinity. 4-[1-(2,5-Dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (9), which displayed: the highest affinity (K
= 6 nM), very strong 5-HT
R antagonistic action (K
= 27 pM), procognitive effects in vivo in novel object recognition (NOR) test in rats, a very good permeability in PAMPA model and satisfying safety in vitro, was identified as the most potent 1,3,5-triazine agent so far, useful as a new lead for further research.</description><subject>Animals</subject><subject>Chlorine - chemistry</subject><subject>Cognition - drug effects</subject><subject>Molecular Docking Simulation</subject><subject>Protein Conformation</subject><subject>Rats</subject><subject>Receptors, Serotonin - chemistry</subject><subject>Receptors, Serotonin - metabolism</subject><subject>Safety</subject><subject>Structure-Activity Relationship</subject><subject>Triazines - chemistry</subject><subject>Triazines - metabolism</subject><subject>Triazines - pharmacology</subject><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNqFj01OwzAUhC0k1JafK6B3gEZyY2LougJ1jbqv3MZJXnH9rGfHKJwGcRRORgp0zWo08400mgsxWzzox0KV1f1UXMV4kFJWWsqJmKpSL1W51DPxueocMXoLsd_FhKm3PkUwvgaH_tUyJArkqB3ARGjMPhFHoAaqYr0BDS8wRpgxDdAQg6dsHXTYdm74JRYWczWvisRo3k87tWXM5kQivGHqIDDtqfX4Ux5NsJxwhOi_PjJmuhGXjXHR3v7ptbh7ftqs1kXod0dbbwPj0fCwPZ9S_xa-ATiGW3I</recordid><startdate>20201001</startdate><enddate>20201001</enddate><creator>Sudoł, Sylwia</creator><creator>Kucwaj-Brysz, Katarzyna</creator><creator>Kurczab, Rafał</creator><creator>Wilczyńska, Natalia</creator><creator>Jastrzębska-Więsek, Magdalena</creator><creator>Satała, Grzegorz</creator><creator>Latacz, Gniewomir</creator><creator>Głuch-Lutwin, Monika</creator><creator>Mordyl, Barbara</creator><creator>Żesławska, Ewa</creator><creator>Nitek, Wojciech</creator><creator>Partyka, Anna</creator><creator>Buzun, Kamila</creator><creator>Doroz-Płonka, Agata</creator><creator>Wesołowska, Anna</creator><creator>Bielawska, Anna</creator><creator>Handzlik, Jadwiga</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20201001</creationdate><title>Chlorine substituents and linker topology as factors of 5-HT 6 R activity for novel highly active 1,3,5-triazine derivatives with procognitive properties in vivo</title><author>Sudoł, Sylwia ; Kucwaj-Brysz, Katarzyna ; Kurczab, Rafał ; Wilczyńska, Natalia ; Jastrzębska-Więsek, Magdalena ; Satała, Grzegorz ; Latacz, Gniewomir ; Głuch-Lutwin, Monika ; Mordyl, Barbara ; Żesławska, Ewa ; Nitek, Wojciech ; Partyka, Anna ; Buzun, Kamila ; Doroz-Płonka, Agata ; Wesołowska, Anna ; Bielawska, Anna ; Handzlik, Jadwiga</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_326932963</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Chlorine - chemistry</topic><topic>Cognition - drug effects</topic><topic>Molecular Docking Simulation</topic><topic>Protein Conformation</topic><topic>Rats</topic><topic>Receptors, Serotonin - chemistry</topic><topic>Receptors, Serotonin - metabolism</topic><topic>Safety</topic><topic>Structure-Activity Relationship</topic><topic>Triazines - chemistry</topic><topic>Triazines - metabolism</topic><topic>Triazines - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sudoł, Sylwia</creatorcontrib><creatorcontrib>Kucwaj-Brysz, Katarzyna</creatorcontrib><creatorcontrib>Kurczab, Rafał</creatorcontrib><creatorcontrib>Wilczyńska, Natalia</creatorcontrib><creatorcontrib>Jastrzębska-Więsek, Magdalena</creatorcontrib><creatorcontrib>Satała, Grzegorz</creatorcontrib><creatorcontrib>Latacz, Gniewomir</creatorcontrib><creatorcontrib>Głuch-Lutwin, Monika</creatorcontrib><creatorcontrib>Mordyl, Barbara</creatorcontrib><creatorcontrib>Żesławska, Ewa</creatorcontrib><creatorcontrib>Nitek, Wojciech</creatorcontrib><creatorcontrib>Partyka, Anna</creatorcontrib><creatorcontrib>Buzun, Kamila</creatorcontrib><creatorcontrib>Doroz-Płonka, Agata</creatorcontrib><creatorcontrib>Wesołowska, Anna</creatorcontrib><creatorcontrib>Bielawska, Anna</creatorcontrib><creatorcontrib>Handzlik, Jadwiga</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sudoł, Sylwia</au><au>Kucwaj-Brysz, Katarzyna</au><au>Kurczab, Rafał</au><au>Wilczyńska, Natalia</au><au>Jastrzębska-Więsek, Magdalena</au><au>Satała, Grzegorz</au><au>Latacz, Gniewomir</au><au>Głuch-Lutwin, Monika</au><au>Mordyl, Barbara</au><au>Żesławska, Ewa</au><au>Nitek, Wojciech</au><au>Partyka, Anna</au><au>Buzun, Kamila</au><au>Doroz-Płonka, Agata</au><au>Wesołowska, Anna</au><au>Bielawska, Anna</au><au>Handzlik, Jadwiga</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chlorine substituents and linker topology as factors of 5-HT 6 R activity for novel highly active 1,3,5-triazine derivatives with procognitive properties in vivo</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2020-10-01</date><risdate>2020</risdate><volume>203</volume><spage>112529</spage><pages>112529-</pages><eissn>1768-3254</eissn><abstract>In the light of recent lines of evidence, 5-HT
R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT
R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HT
R ligands. The new compounds were rationally designed as modifications of lead, 4-(1-(2-chlorophenoxy)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (1), involving an introduction of: (i) two chlorines at benzene ring and (ii) varied linkers joining the triazine ring to aromatic ethers. Synthesis, in vitro and in vivo biological tests and computer-aided SAR analysis for 19 new compounds were carried out. Most of the new triazines displayed high affinity (K
< 100 nM) and selectivity towards 5-HT
R, with respect to 5-HT
R, 5-HT
R and D
R. The crystallography-supported docking studies, including quantum-polarized ligand docking (QPLD), indicated that chlorine atoms may be involved in different type of halogen bonding, however, the linker properties seem to predominately affect the 5-HT
R affinity. 4-[1-(2,5-Dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (9), which displayed: the highest affinity (K
= 6 nM), very strong 5-HT
R antagonistic action (K
= 27 pM), procognitive effects in vivo in novel object recognition (NOR) test in rats, a very good permeability in PAMPA model and satisfying safety in vitro, was identified as the most potent 1,3,5-triazine agent so far, useful as a new lead for further research.</abstract><cop>France</cop><pmid>32693296</pmid></addata></record> |
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| ispartof | European journal of medicinal chemistry, 2020-10, Vol.203, p.112529 |
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| subjects | Animals Chlorine - chemistry Cognition - drug effects Molecular Docking Simulation Protein Conformation Rats Receptors, Serotonin - chemistry Receptors, Serotonin - metabolism Safety Structure-Activity Relationship Triazines - chemistry Triazines - metabolism Triazines - pharmacology |
| title | Chlorine substituents and linker topology as factors of 5-HT 6 R activity for novel highly active 1,3,5-triazine derivatives with procognitive properties in vivo |
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