Benzimidazole Derivatives as New Serotonin 5-HT6 Receptor Antagonists. Molecular Mechanisms of Receptor Inactivation
On the basis of our previously described pharmacophore model for serotonin 5-HT6 receptor (5-HT6R) antagonists, we have designed, synthesized, and pharmacologically characterized a series of benzimidazole derivatives 1−20 that represent a new family of potent antagonists at the human 5-HT6R. Site-di...
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| Veröffentlicht in: | Journal of medicinal chemistry 2010-02, Vol.53 (3), p.1357-1369 |
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| container_title | Journal of medicinal chemistry |
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| creator | de la Fuente, Tania Martín-Fontecha, Mar Sallander, Jessica Benhamú, Bellinda Campillo, Mercedes Medina, Rocío A Pellissier, Lucie P Claeysen, Sylvie Dumuis, Aline Pardo, Leonardo López-Rodríguez, María L |
| description | On the basis of our previously described pharmacophore model for serotonin 5-HT6 receptor (5-HT6R) antagonists, we have designed, synthesized, and pharmacologically characterized a series of benzimidazole derivatives 1−20 that represent a new family of potent antagonists at the human 5-HT6R. Site-directed mutagenesis and a β2-adrenoceptor-based homology model of the 5-HT6R were used to predict the mode of binding of antagonist SB-258585 and the new synthesized ligands. Substitution of W6.48, F6.52, or N6.55 by Ala fully impedes compound 4 to block 5-HT-induced activation. Thus, we propose that D3.32 in TM 3 anchors the protonated piperazine ring, the benzimidazole ring expands parallel to EL 2 to hydrogen bond N6.55 in TM 6, and the aromatic ring is placed between TMs 3 and 5 in CH2-containing compounds and between TMs 3 and 6 in CO-containing compounds. This combined experimental and computational study has permitted to propose the molecular mechanisms by which the new benzimidazole derivatives act as 5-HT6R antagonists. |
| doi_str_mv | 10.1021/jm901672k |
| format | Article |
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Molecular Mechanisms of Receptor Inactivation</title><source>MEDLINE</source><source>ACS Publications</source><creator>de la Fuente, Tania ; Martín-Fontecha, Mar ; Sallander, Jessica ; Benhamú, Bellinda ; Campillo, Mercedes ; Medina, Rocío A ; Pellissier, Lucie P ; Claeysen, Sylvie ; Dumuis, Aline ; Pardo, Leonardo ; López-Rodríguez, María L</creator><creatorcontrib>de la Fuente, Tania ; Martín-Fontecha, Mar ; Sallander, Jessica ; Benhamú, Bellinda ; Campillo, Mercedes ; Medina, Rocío A ; Pellissier, Lucie P ; Claeysen, Sylvie ; Dumuis, Aline ; Pardo, Leonardo ; López-Rodríguez, María L</creatorcontrib><description>On the basis of our previously described pharmacophore model for serotonin 5-HT6 receptor (5-HT6R) antagonists, we have designed, synthesized, and pharmacologically characterized a series of benzimidazole derivatives 1−20 that represent a new family of potent antagonists at the human 5-HT6R. Site-directed mutagenesis and a β2-adrenoceptor-based homology model of the 5-HT6R were used to predict the mode of binding of antagonist SB-258585 and the new synthesized ligands. Substitution of W6.48, F6.52, or N6.55 by Ala fully impedes compound 4 to block 5-HT-induced activation. Thus, we propose that D3.32 in TM 3 anchors the protonated piperazine ring, the benzimidazole ring expands parallel to EL 2 to hydrogen bond N6.55 in TM 6, and the aromatic ring is placed between TMs 3 and 5 in CH2-containing compounds and between TMs 3 and 6 in CO-containing compounds. This combined experimental and computational study has permitted to propose the molecular mechanisms by which the new benzimidazole derivatives act as 5-HT6R antagonists.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm901672k</identifier><identifier>PMID: 20078106</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Animals ; Benzimidazoles - chemical synthesis ; Benzimidazoles - chemistry ; Benzimidazoles - pharmacology ; Binding, Competitive ; Biological and medical sciences ; Cells, Cultured ; Cercopithecus aethiops ; Computer Simulation ; COS Cells ; Cyclic AMP - metabolism ; Enzyme-Linked Immunosorbent Assay ; Humans ; Kidney - cytology ; Kidney - drug effects ; Medical sciences ; Molecular Structure ; Mutagenesis, Site-Directed ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Protein Conformation ; Radioligand Assay ; Receptors, Serotonin - chemistry ; Receptors, Serotonin - genetics ; Receptors, Serotonin - metabolism ; Serotonin Antagonists - chemical synthesis ; Serotonin Antagonists - chemistry ; Serotonin Antagonists - pharmacology ; Serotoninergic system ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2010-02, Vol.53 (3), p.1357-1369</ispartof><rights>Copyright © 2010 American Chemical Society</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm901672k$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm901672k$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,777,781,27057,27905,27906,56719,56769</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22454141$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20078106$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>de la Fuente, Tania</creatorcontrib><creatorcontrib>Martín-Fontecha, Mar</creatorcontrib><creatorcontrib>Sallander, Jessica</creatorcontrib><creatorcontrib>Benhamú, Bellinda</creatorcontrib><creatorcontrib>Campillo, Mercedes</creatorcontrib><creatorcontrib>Medina, Rocío A</creatorcontrib><creatorcontrib>Pellissier, Lucie P</creatorcontrib><creatorcontrib>Claeysen, Sylvie</creatorcontrib><creatorcontrib>Dumuis, Aline</creatorcontrib><creatorcontrib>Pardo, Leonardo</creatorcontrib><creatorcontrib>López-Rodríguez, María L</creatorcontrib><title>Benzimidazole Derivatives as New Serotonin 5-HT6 Receptor Antagonists. Molecular Mechanisms of Receptor Inactivation</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>On the basis of our previously described pharmacophore model for serotonin 5-HT6 receptor (5-HT6R) antagonists, we have designed, synthesized, and pharmacologically characterized a series of benzimidazole derivatives 1−20 that represent a new family of potent antagonists at the human 5-HT6R. Site-directed mutagenesis and a β2-adrenoceptor-based homology model of the 5-HT6R were used to predict the mode of binding of antagonist SB-258585 and the new synthesized ligands. Substitution of W6.48, F6.52, or N6.55 by Ala fully impedes compound 4 to block 5-HT-induced activation. Thus, we propose that D3.32 in TM 3 anchors the protonated piperazine ring, the benzimidazole ring expands parallel to EL 2 to hydrogen bond N6.55 in TM 6, and the aromatic ring is placed between TMs 3 and 5 in CH2-containing compounds and between TMs 3 and 6 in CO-containing compounds. This combined experimental and computational study has permitted to propose the molecular mechanisms by which the new benzimidazole derivatives act as 5-HT6R antagonists.</description><subject>Animals</subject><subject>Benzimidazoles - chemical synthesis</subject><subject>Benzimidazoles - chemistry</subject><subject>Benzimidazoles - pharmacology</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Cercopithecus aethiops</subject><subject>Computer Simulation</subject><subject>COS Cells</subject><subject>Cyclic AMP - metabolism</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Humans</subject><subject>Kidney - cytology</subject><subject>Kidney - drug effects</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>Mutagenesis, Site-Directed</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Conformation</subject><subject>Radioligand Assay</subject><subject>Receptors, Serotonin - chemistry</subject><subject>Receptors, Serotonin - genetics</subject><subject>Receptors, Serotonin - metabolism</subject><subject>Serotonin Antagonists - chemical synthesis</subject><subject>Serotonin Antagonists - chemistry</subject><subject>Serotonin Antagonists - pharmacology</subject><subject>Serotoninergic system</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkM1PwkAQxTdGI4ge_AfMXjwWZz-6XY6IH5CAJornZrrdapFuSXfByF9vVZTTJG9-8zLvEXLOoM-As6tFNQCmEv5-QLos5hBJDfKQdAE4j7jiokNOvF8AgGBcHJMOB0g0A9Ul4dq6bVmVOW7rpaU3tik3GMqN9RQ9fbAf9Nk2dahd6WgcjeeKPlljV6Fu6NAFfG0XPvg-nbXXZr3Ehs6secNWrTytiz09cWjCj3ftTslRgUtvz3azR17ubuejcTR9vJ-MhtMIRcJClAltVI5ZoTWTOSRoLWDOixi0ska20oDlIlGJzKwAZbTSlkmdcSiSgZBG9MjFr-9qnVU2T1dNWWHzmf7Fb4HLHYDe4LJo0JnS7zkuY8kk23NofLqo141r304ZpN_1p__1iy-7cHVe</recordid><startdate>20100211</startdate><enddate>20100211</enddate><creator>de la Fuente, Tania</creator><creator>Martín-Fontecha, Mar</creator><creator>Sallander, Jessica</creator><creator>Benhamú, Bellinda</creator><creator>Campillo, Mercedes</creator><creator>Medina, Rocío A</creator><creator>Pellissier, Lucie P</creator><creator>Claeysen, Sylvie</creator><creator>Dumuis, Aline</creator><creator>Pardo, Leonardo</creator><creator>López-Rodríguez, María L</creator><general>American Chemical Society</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20100211</creationdate><title>Benzimidazole Derivatives as New Serotonin 5-HT6 Receptor Antagonists. Molecular Mechanisms of Receptor Inactivation</title><author>de la Fuente, Tania ; Martín-Fontecha, Mar ; Sallander, Jessica ; Benhamú, Bellinda ; Campillo, Mercedes ; Medina, Rocío A ; Pellissier, Lucie P ; Claeysen, Sylvie ; Dumuis, Aline ; Pardo, Leonardo ; López-Rodríguez, María L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a371t-b38c6dabf8814d07aee0ad2f5086ec44d091d37674be306c868e148b20f7934c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Benzimidazoles - chemical synthesis</topic><topic>Benzimidazoles - chemistry</topic><topic>Benzimidazoles - pharmacology</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Cercopithecus aethiops</topic><topic>Computer Simulation</topic><topic>COS Cells</topic><topic>Cyclic AMP - metabolism</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Humans</topic><topic>Kidney - cytology</topic><topic>Kidney - drug effects</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>Mutagenesis, Site-Directed</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Conformation</topic><topic>Radioligand Assay</topic><topic>Receptors, Serotonin - chemistry</topic><topic>Receptors, Serotonin - genetics</topic><topic>Receptors, Serotonin - metabolism</topic><topic>Serotonin Antagonists - chemical synthesis</topic><topic>Serotonin Antagonists - chemistry</topic><topic>Serotonin Antagonists - pharmacology</topic><topic>Serotoninergic system</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>de la Fuente, Tania</creatorcontrib><creatorcontrib>Martín-Fontecha, Mar</creatorcontrib><creatorcontrib>Sallander, Jessica</creatorcontrib><creatorcontrib>Benhamú, Bellinda</creatorcontrib><creatorcontrib>Campillo, Mercedes</creatorcontrib><creatorcontrib>Medina, Rocío A</creatorcontrib><creatorcontrib>Pellissier, Lucie P</creatorcontrib><creatorcontrib>Claeysen, Sylvie</creatorcontrib><creatorcontrib>Dumuis, Aline</creatorcontrib><creatorcontrib>Pardo, Leonardo</creatorcontrib><creatorcontrib>López-Rodríguez, María L</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>de la Fuente, Tania</au><au>Martín-Fontecha, Mar</au><au>Sallander, Jessica</au><au>Benhamú, Bellinda</au><au>Campillo, Mercedes</au><au>Medina, Rocío A</au><au>Pellissier, Lucie P</au><au>Claeysen, Sylvie</au><au>Dumuis, Aline</au><au>Pardo, Leonardo</au><au>López-Rodríguez, María L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Benzimidazole Derivatives as New Serotonin 5-HT6 Receptor Antagonists. Molecular Mechanisms of Receptor Inactivation</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2010-02-11</date><risdate>2010</risdate><volume>53</volume><issue>3</issue><spage>1357</spage><epage>1369</epage><pages>1357-1369</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>On the basis of our previously described pharmacophore model for serotonin 5-HT6 receptor (5-HT6R) antagonists, we have designed, synthesized, and pharmacologically characterized a series of benzimidazole derivatives 1−20 that represent a new family of potent antagonists at the human 5-HT6R. Site-directed mutagenesis and a β2-adrenoceptor-based homology model of the 5-HT6R were used to predict the mode of binding of antagonist SB-258585 and the new synthesized ligands. Substitution of W6.48, F6.52, or N6.55 by Ala fully impedes compound 4 to block 5-HT-induced activation. Thus, we propose that D3.32 in TM 3 anchors the protonated piperazine ring, the benzimidazole ring expands parallel to EL 2 to hydrogen bond N6.55 in TM 6, and the aromatic ring is placed between TMs 3 and 5 in CH2-containing compounds and between TMs 3 and 6 in CO-containing compounds. This combined experimental and computational study has permitted to propose the molecular mechanisms by which the new benzimidazole derivatives act as 5-HT6R antagonists.</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>20078106</pmid><doi>10.1021/jm901672k</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2010-02, Vol.53 (3), p.1357-1369 |
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| subjects | Animals Benzimidazoles - chemical synthesis Benzimidazoles - chemistry Benzimidazoles - pharmacology Binding, Competitive Biological and medical sciences Cells, Cultured Cercopithecus aethiops Computer Simulation COS Cells Cyclic AMP - metabolism Enzyme-Linked Immunosorbent Assay Humans Kidney - cytology Kidney - drug effects Medical sciences Molecular Structure Mutagenesis, Site-Directed Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Protein Conformation Radioligand Assay Receptors, Serotonin - chemistry Receptors, Serotonin - genetics Receptors, Serotonin - metabolism Serotonin Antagonists - chemical synthesis Serotonin Antagonists - chemistry Serotonin Antagonists - pharmacology Serotoninergic system Structure-Activity Relationship |
| title | Benzimidazole Derivatives as New Serotonin 5-HT6 Receptor Antagonists. Molecular Mechanisms of Receptor Inactivation |
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