Identification of Highly Selective Orexin 1 Receptor Antagonists Driven by Structure-Based Design
OX1 receptor antagonists are of interest to treat, for example, substance abuse disorders, personality disorders, eating disorders, or anxiety-related disorders. However, known dual OX1/OX2 receptor antagonists are not suitable due to their sleep-inducing effects; therefore, we were interested in id...
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| Veröffentlicht in: | Journal of chemical information and modeling 2021-12, Vol.61 (12), p.5893-5905 |
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| container_issue | 12 |
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| container_title | Journal of chemical information and modeling |
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| creator | Lessel, Uta Ferrara, Marco Heine, Niklas Marelli, Chiara Carrettoni, Laura Pfau, Roland Schmidt, Esther Riether, Doris |
| description | OX1 receptor antagonists are of interest to treat, for example, substance abuse disorders, personality disorders, eating disorders, or anxiety-related disorders. However, known dual OX1/OX2 receptor antagonists are not suitable due to their sleep-inducing effects; therefore, we were interested in identifying a highly OX1 selective antagonist with a sufficient window to OX2-mediated effects. Herein, we describe the design of highly selective OX1 receptor antagonists driven by the X-ray structure of OX1 with suvorexant, a dual OX1/OX2 receptor antagonist. Moderately selective OX1 antagonists comprising a [2.2.1]-bicyclic scaffold served as our starting point. Based on our binding mode hypothesis, we postulated which part of the scaffold points toward one of the regions where the two binding pockets differ. Structural changes in this part resulted in a modified core with higher inherent selectivity compared to the [2.2.1]-bicyclic template. The structure-based design, synthesis, and hit-to-lead evaluation of this novel OX1 receptor-selective scaffold are discussed herein. |
| doi_str_mv | 10.1021/acs.jcim.1c01055 |
| format | Article |
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However, known dual OX1/OX2 receptor antagonists are not suitable due to their sleep-inducing effects; therefore, we were interested in identifying a highly OX1 selective antagonist with a sufficient window to OX2-mediated effects. Herein, we describe the design of highly selective OX1 receptor antagonists driven by the X-ray structure of OX1 with suvorexant, a dual OX1/OX2 receptor antagonist. Moderately selective OX1 antagonists comprising a [2.2.1]-bicyclic scaffold served as our starting point. Based on our binding mode hypothesis, we postulated which part of the scaffold points toward one of the regions where the two binding pockets differ. Structural changes in this part resulted in a modified core with higher inherent selectivity compared to the [2.2.1]-bicyclic template. The structure-based design, synthesis, and hit-to-lead evaluation of this novel OX1 receptor-selective scaffold are discussed herein.</description><identifier>ISSN: 1549-9596</identifier><identifier>EISSN: 1549-960X</identifier><identifier>DOI: 10.1021/acs.jcim.1c01055</identifier><identifier>PMID: 34817173</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Binding ; Computational Chemistry ; Mental disorders ; Orexin Receptors - metabolism ; Orexins ; Receptors ; Scaffolds ; Selectivity</subject><ispartof>Journal of chemical information and modeling, 2021-12, Vol.61 (12), p.5893-5905</ispartof><rights>2021 American Chemical Society</rights><rights>Copyright American Chemical Society Dec 27, 2021</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a364t-a38dda108c1c881f2dfa850d139534cce2a1548f49365ebdd2757088f0b2e1873</citedby><cites>FETCH-LOGICAL-a364t-a38dda108c1c881f2dfa850d139534cce2a1548f49365ebdd2757088f0b2e1873</cites><orcidid>0000-0002-1698-6017 ; 0000-0002-8535-2501</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jcim.1c01055$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jcim.1c01055$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56717,56767</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34817173$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lessel, Uta</creatorcontrib><creatorcontrib>Ferrara, Marco</creatorcontrib><creatorcontrib>Heine, Niklas</creatorcontrib><creatorcontrib>Marelli, Chiara</creatorcontrib><creatorcontrib>Carrettoni, Laura</creatorcontrib><creatorcontrib>Pfau, Roland</creatorcontrib><creatorcontrib>Schmidt, Esther</creatorcontrib><creatorcontrib>Riether, Doris</creatorcontrib><title>Identification of Highly Selective Orexin 1 Receptor Antagonists Driven by Structure-Based Design</title><title>Journal of chemical information and modeling</title><addtitle>J. Chem. Inf. Model</addtitle><description>OX1 receptor antagonists are of interest to treat, for example, substance abuse disorders, personality disorders, eating disorders, or anxiety-related disorders. However, known dual OX1/OX2 receptor antagonists are not suitable due to their sleep-inducing effects; therefore, we were interested in identifying a highly OX1 selective antagonist with a sufficient window to OX2-mediated effects. Herein, we describe the design of highly selective OX1 receptor antagonists driven by the X-ray structure of OX1 with suvorexant, a dual OX1/OX2 receptor antagonist. Moderately selective OX1 antagonists comprising a [2.2.1]-bicyclic scaffold served as our starting point. Based on our binding mode hypothesis, we postulated which part of the scaffold points toward one of the regions where the two binding pockets differ. Structural changes in this part resulted in a modified core with higher inherent selectivity compared to the [2.2.1]-bicyclic template. 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Chem. Inf. Model</addtitle><date>2021-12-27</date><risdate>2021</risdate><volume>61</volume><issue>12</issue><spage>5893</spage><epage>5905</epage><pages>5893-5905</pages><issn>1549-9596</issn><eissn>1549-960X</eissn><abstract>OX1 receptor antagonists are of interest to treat, for example, substance abuse disorders, personality disorders, eating disorders, or anxiety-related disorders. However, known dual OX1/OX2 receptor antagonists are not suitable due to their sleep-inducing effects; therefore, we were interested in identifying a highly OX1 selective antagonist with a sufficient window to OX2-mediated effects. Herein, we describe the design of highly selective OX1 receptor antagonists driven by the X-ray structure of OX1 with suvorexant, a dual OX1/OX2 receptor antagonist. Moderately selective OX1 antagonists comprising a [2.2.1]-bicyclic scaffold served as our starting point. 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| subjects | Binding Computational Chemistry Mental disorders Orexin Receptors - metabolism Orexins Receptors Scaffolds Selectivity |
| title | Identification of Highly Selective Orexin 1 Receptor Antagonists Driven by Structure-Based Design |
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