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Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR(7) Allosteric Agonist
[Image: see text] The low affinity metabotropic glutamate receptor mGluR(7) has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present t...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
American Chemical Society
2023
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10107911/ https://www.ncbi.nlm.nih.gov/pubmed/37077399 http://dx.doi.org/10.1021/acsmedchemlett.2c00529 |
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| author | Dickson, Louise Teall, Martin Chevalier, Elodie Cheung, Toni Liwicki, Gemma M. Mack, Stephen Stephenson, Anne White, Kathryn Fosbeary, Richard Harrison, David C. Brice, Nicola L. Doyle, Kevin Ciccocioppo, Roberto Wu, Chaobo Almond, Sarah Patel, Toshal R. Mitchell, Philip Barnes, Matt Ayscough, Andrew P. Dawson, Lee A. Carlton, Mark Bürli, Roland W. |
| author_facet | Dickson, Louise Teall, Martin Chevalier, Elodie Cheung, Toni Liwicki, Gemma M. Mack, Stephen Stephenson, Anne White, Kathryn Fosbeary, Richard Harrison, David C. Brice, Nicola L. Doyle, Kevin Ciccocioppo, Roberto Wu, Chaobo Almond, Sarah Patel, Toshal R. Mitchell, Philip Barnes, Matt Ayscough, Andrew P. Dawson, Lee A. Carlton, Mark Bürli, Roland W. |
| author_sort | Dickson, Louise |
| collection | PubMed |
| description | [Image: see text] The low affinity metabotropic glutamate receptor mGluR(7) has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR(7) agonists. Of particular interest is the chromane CVN636, a potent (EC(50) 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR(7) compared to not only other mGluRs, but also a broad range of targets. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. CVN636 thus has potential to progress as a drug candidate in CNS disorders involving mGluR(7) and glutamatergic dysfunction. |
| format | Online Article Text |
| id | pubmed-10107911 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2023 |
| publisher | American Chemical Society |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-101079112023-04-18 Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR(7) Allosteric Agonist Dickson, Louise Teall, Martin Chevalier, Elodie Cheung, Toni Liwicki, Gemma M. Mack, Stephen Stephenson, Anne White, Kathryn Fosbeary, Richard Harrison, David C. Brice, Nicola L. Doyle, Kevin Ciccocioppo, Roberto Wu, Chaobo Almond, Sarah Patel, Toshal R. Mitchell, Philip Barnes, Matt Ayscough, Andrew P. Dawson, Lee A. Carlton, Mark Bürli, Roland W. ACS Med Chem Lett [Image: see text] The low affinity metabotropic glutamate receptor mGluR(7) has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR(7) agonists. Of particular interest is the chromane CVN636, a potent (EC(50) 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR(7) compared to not only other mGluRs, but also a broad range of targets. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. CVN636 thus has potential to progress as a drug candidate in CNS disorders involving mGluR(7) and glutamatergic dysfunction. American Chemical Society 2023-03-02 /pmc/articles/PMC10107911/ /pubmed/37077399 http://dx.doi.org/10.1021/acsmedchemlett.2c00529 Text en © 2023 American Chemical Society https://pubs.acs.org/page/policy/termsofuse.htmlMade available for a limited time for personal research and study only License (https://pubs.acs.org/page/policy/termsofuse.html) . |
| spellingShingle | Dickson, Louise Teall, Martin Chevalier, Elodie Cheung, Toni Liwicki, Gemma M. Mack, Stephen Stephenson, Anne White, Kathryn Fosbeary, Richard Harrison, David C. Brice, Nicola L. Doyle, Kevin Ciccocioppo, Roberto Wu, Chaobo Almond, Sarah Patel, Toshal R. Mitchell, Philip Barnes, Matt Ayscough, Andrew P. Dawson, Lee A. Carlton, Mark Bürli, Roland W. Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR(7) Allosteric Agonist |
| title | Discovery
of CVN636: A Highly Potent,
Selective, and CNS Penetrant mGluR(7) Allosteric Agonist |
| title_full | Discovery
of CVN636: A Highly Potent,
Selective, and CNS Penetrant mGluR(7) Allosteric Agonist |
| title_fullStr | Discovery
of CVN636: A Highly Potent,
Selective, and CNS Penetrant mGluR(7) Allosteric Agonist |
| title_full_unstemmed | Discovery
of CVN636: A Highly Potent,
Selective, and CNS Penetrant mGluR(7) Allosteric Agonist |
| title_short | Discovery
of CVN636: A Highly Potent,
Selective, and CNS Penetrant mGluR(7) Allosteric Agonist |
| title_sort | discovery
of cvn636: a highly potent,
selective, and cns penetrant mglur(7) allosteric agonist |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10107911/ https://www.ncbi.nlm.nih.gov/pubmed/37077399 http://dx.doi.org/10.1021/acsmedchemlett.2c00529 |
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