Triazine-Based Vanilloid 1 Receptor Open Channel Blockers: Design, Synthesis, Evaluation, and SAR Analysis
The thermosensory transient receptor potential vanilloid 1 channel (TRPV1) is a polymodal receptor activated by physical and chemical stimuli. TRPV1 activity is drastically potentiated by proinflammatory agents released upon tissue damage. Given the pivotal role of TRPV1 in human pain, there is pres...
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Veröffentlicht in: | Journal of medicinal chemistry 2011-11, Vol.54 (21), p.7441-7452 |
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container_title | Journal of medicinal chemistry |
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creator | Vidal-Mosquera, Miquel Fernández-Carvajal, Asia Moure, Alejandra Valente, Pierluigi Planells-Cases, Rosa González-Ros, José M Bujons, Jordi Ferrer-Montiel, Antonio Messeguer, Angel |
description | The thermosensory transient receptor potential vanilloid 1 channel (TRPV1) is a polymodal receptor activated by physical and chemical stimuli. TRPV1 activity is drastically potentiated by proinflammatory agents released upon tissue damage. Given the pivotal role of TRPV1 in human pain, there is pressing need for improved TRPV1 antagonists, the development of which will require identification of new pharmacophore scaffolds. Uncompetitive antagonists acting as open-channel blockers might serve as activity-dependent blockers that preferentially modulate the activity of overactive channels, thus displaying fewer side effects than their competitive counterparts. Herein we report the design, synthesis, biological evaluation, and SAR analysis of a family of triazine-based compounds acting as TRPV1 uncompetitive antagonists. We identified the triazine 8aA as a potent, pure antagonist that inhibits TRPV1 channel activity with nanomolar efficacy and strong voltage dependency. It represents a new class of activity-dependent TRPV1 antagonists and may serve as the basis for lead optimization in the development of new analgesics. |
doi_str_mv | 10.1021/jm200981s |
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TRPV1 activity is drastically potentiated by proinflammatory agents released upon tissue damage. Given the pivotal role of TRPV1 in human pain, there is pressing need for improved TRPV1 antagonists, the development of which will require identification of new pharmacophore scaffolds. Uncompetitive antagonists acting as open-channel blockers might serve as activity-dependent blockers that preferentially modulate the activity of overactive channels, thus displaying fewer side effects than their competitive counterparts. Herein we report the design, synthesis, biological evaluation, and SAR analysis of a family of triazine-based compounds acting as TRPV1 uncompetitive antagonists. We identified the triazine 8aA as a potent, pure antagonist that inhibits TRPV1 channel activity with nanomolar efficacy and strong voltage dependency. It represents a new class of activity-dependent TRPV1 antagonists and may serve as the basis for lead optimization in the development of new analgesics.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm200981s</identifier><identifier>PMID: 21950613</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Analgesics - chemical synthesis ; Analgesics - chemistry ; Analgesics - pharmacology ; Animals ; Binding Sites ; Drug Design ; Female ; Oocytes - drug effects ; Oocytes - physiology ; Patch-Clamp Techniques ; Rats ; Recombinant Proteins - antagonists & inhibitors ; Structure-Activity Relationship ; Triazines - chemical synthesis ; Triazines - chemistry ; Triazines - pharmacology ; TRPV Cation Channels - antagonists & inhibitors ; Xenopus</subject><ispartof>Journal of medicinal chemistry, 2011-11, Vol.54 (21), p.7441-7452</ispartof><rights>Copyright © 2011 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a406t-359c2f2b32c5b9b9c63044c796fbecba6b1237581889b4197fd5b3dfd93c26ca3</citedby><cites>FETCH-LOGICAL-a406t-359c2f2b32c5b9b9c63044c796fbecba6b1237581889b4197fd5b3dfd93c26ca3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm200981s$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm200981s$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21950613$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vidal-Mosquera, Miquel</creatorcontrib><creatorcontrib>Fernández-Carvajal, Asia</creatorcontrib><creatorcontrib>Moure, Alejandra</creatorcontrib><creatorcontrib>Valente, Pierluigi</creatorcontrib><creatorcontrib>Planells-Cases, Rosa</creatorcontrib><creatorcontrib>González-Ros, José M</creatorcontrib><creatorcontrib>Bujons, Jordi</creatorcontrib><creatorcontrib>Ferrer-Montiel, Antonio</creatorcontrib><creatorcontrib>Messeguer, Angel</creatorcontrib><title>Triazine-Based Vanilloid 1 Receptor Open Channel Blockers: Design, Synthesis, Evaluation, and SAR Analysis</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The thermosensory transient receptor potential vanilloid 1 channel (TRPV1) is a polymodal receptor activated by physical and chemical stimuli. TRPV1 activity is drastically potentiated by proinflammatory agents released upon tissue damage. Given the pivotal role of TRPV1 in human pain, there is pressing need for improved TRPV1 antagonists, the development of which will require identification of new pharmacophore scaffolds. Uncompetitive antagonists acting as open-channel blockers might serve as activity-dependent blockers that preferentially modulate the activity of overactive channels, thus displaying fewer side effects than their competitive counterparts. Herein we report the design, synthesis, biological evaluation, and SAR analysis of a family of triazine-based compounds acting as TRPV1 uncompetitive antagonists. We identified the triazine 8aA as a potent, pure antagonist that inhibits TRPV1 channel activity with nanomolar efficacy and strong voltage dependency. It represents a new class of activity-dependent TRPV1 antagonists and may serve as the basis for lead optimization in the development of new analgesics.</description><subject>Analgesics - chemical synthesis</subject><subject>Analgesics - chemistry</subject><subject>Analgesics - pharmacology</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Drug Design</subject><subject>Female</subject><subject>Oocytes - drug effects</subject><subject>Oocytes - physiology</subject><subject>Patch-Clamp Techniques</subject><subject>Rats</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><subject>Triazines - chemical synthesis</subject><subject>Triazines - chemistry</subject><subject>Triazines - pharmacology</subject><subject>TRPV Cation Channels - antagonists & inhibitors</subject><subject>Xenopus</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMtKAzEUhoMotlYXvoBkIyJ0NJe5xV1b6wUKhba6HZJMxs6YZsZkRqhPb6TalatzOOfjh_8D4ByjG4wIvq02BCGWYncA-jgiKAhTFB6CPkKEBCQmtAdOnKsQQhQTegx6BLMIxZj2QbWyJf8qjQrG3KkcvnJTal2XOcRwoaRq2trCeaMMnKy5MUrDsa7lu7LuDt4rV76ZIVxuTbv2uxvC6SfXHW_L2p-5yeFytIAjw_XWf0_BUcG1U2e_cwBeHqaryVMwmz8-T0azgIcobgMaMUkKIiiRkWCCyZiiMJQJiwuhpOCx8B2SKMVpykSIWVLkkaB5kTMqSSw5HYCrXW5j649OuTbblE4qrblRdecyhgilaUKYJ693pLS1c1YVWWPLDbfbDKPsx2y2N-vZi9_UTmxUvif_VHrgcgdw6bKq7qyv7f4J-gbumX7O</recordid><startdate>20111110</startdate><enddate>20111110</enddate><creator>Vidal-Mosquera, Miquel</creator><creator>Fernández-Carvajal, Asia</creator><creator>Moure, Alejandra</creator><creator>Valente, Pierluigi</creator><creator>Planells-Cases, Rosa</creator><creator>González-Ros, José M</creator><creator>Bujons, Jordi</creator><creator>Ferrer-Montiel, Antonio</creator><creator>Messeguer, Angel</creator><general>American Chemical Society</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>7X8</scope></search><sort><creationdate>20111110</creationdate><title>Triazine-Based Vanilloid 1 Receptor Open Channel Blockers: Design, Synthesis, Evaluation, and SAR Analysis</title><author>Vidal-Mosquera, Miquel ; Fernández-Carvajal, Asia ; Moure, Alejandra ; Valente, Pierluigi ; Planells-Cases, Rosa ; González-Ros, José M ; Bujons, Jordi ; Ferrer-Montiel, Antonio ; Messeguer, Angel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a406t-359c2f2b32c5b9b9c63044c796fbecba6b1237581889b4197fd5b3dfd93c26ca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Analgesics - chemical synthesis</topic><topic>Analgesics - chemistry</topic><topic>Analgesics - pharmacology</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Drug Design</topic><topic>Female</topic><topic>Oocytes - drug effects</topic><topic>Oocytes - physiology</topic><topic>Patch-Clamp Techniques</topic><topic>Rats</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><topic>Triazines - chemical synthesis</topic><topic>Triazines - chemistry</topic><topic>Triazines - pharmacology</topic><topic>TRPV Cation Channels - antagonists & inhibitors</topic><topic>Xenopus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vidal-Mosquera, Miquel</creatorcontrib><creatorcontrib>Fernández-Carvajal, Asia</creatorcontrib><creatorcontrib>Moure, Alejandra</creatorcontrib><creatorcontrib>Valente, Pierluigi</creatorcontrib><creatorcontrib>Planells-Cases, Rosa</creatorcontrib><creatorcontrib>González-Ros, José M</creatorcontrib><creatorcontrib>Bujons, Jordi</creatorcontrib><creatorcontrib>Ferrer-Montiel, Antonio</creatorcontrib><creatorcontrib>Messeguer, Angel</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vidal-Mosquera, Miquel</au><au>Fernández-Carvajal, Asia</au><au>Moure, Alejandra</au><au>Valente, Pierluigi</au><au>Planells-Cases, Rosa</au><au>González-Ros, José M</au><au>Bujons, Jordi</au><au>Ferrer-Montiel, Antonio</au><au>Messeguer, Angel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Triazine-Based Vanilloid 1 Receptor Open Channel Blockers: Design, Synthesis, Evaluation, and SAR Analysis</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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subjects | Analgesics - chemical synthesis Analgesics - chemistry Analgesics - pharmacology Animals Binding Sites Drug Design Female Oocytes - drug effects Oocytes - physiology Patch-Clamp Techniques Rats Recombinant Proteins - antagonists & inhibitors Structure-Activity Relationship Triazines - chemical synthesis Triazines - chemistry Triazines - pharmacology TRPV Cation Channels - antagonists & inhibitors Xenopus |
title | Triazine-Based Vanilloid 1 Receptor Open Channel Blockers: Design, Synthesis, Evaluation, and SAR Analysis |
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