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Synthesis and in Vitro and in Vivo Characterization of Highly β(1)-Selective β-Adrenoceptor Partial Agonists
[Image: see text] β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β(1)-selective molecules exist. To...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2013
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694353/ https://www.ncbi.nlm.nih.gov/pubmed/23614528 http://dx.doi.org/10.1021/jm400348g |
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author | Mistry, Shailesh N. Baker, Jillian G Fischer, Peter M Hill, Stephen J Gardiner, Sheila M Kellam, Barrie |
author_facet | Mistry, Shailesh N. Baker, Jillian G Fischer, Peter M Hill, Stephen J Gardiner, Sheila M Kellam, Barrie |
author_sort | Mistry, Shailesh N. |
collection | PubMed |
description | [Image: see text] β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β(1)-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),1 a selective β(1)-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1’s aromatic nitrile afforded 19, a ligand with similar β(1)-adrenoceptor selectivity and partial agonism (log K(D) of −7.75 and −5.15 as an antagonist of functional β(1)- and β(2)-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β(1))). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and β(1)-selectivity. |
format | Online Article Text |
id | pubmed-3694353 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-36943532013-06-28 Synthesis and in Vitro and in Vivo Characterization of Highly β(1)-Selective β-Adrenoceptor Partial Agonists Mistry, Shailesh N. Baker, Jillian G Fischer, Peter M Hill, Stephen J Gardiner, Sheila M Kellam, Barrie J Med Chem [Image: see text] β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β(1)-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),1 a selective β(1)-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1’s aromatic nitrile afforded 19, a ligand with similar β(1)-adrenoceptor selectivity and partial agonism (log K(D) of −7.75 and −5.15 as an antagonist of functional β(1)- and β(2)-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β(1))). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and β(1)-selectivity. American Chemical Society 2013-04-24 2013-05-23 /pmc/articles/PMC3694353/ /pubmed/23614528 http://dx.doi.org/10.1021/jm400348g Text en Copyright © 2013 American Chemical Society Terms of Use CC-BY (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) |
spellingShingle | Mistry, Shailesh N. Baker, Jillian G Fischer, Peter M Hill, Stephen J Gardiner, Sheila M Kellam, Barrie Synthesis and in Vitro and in Vivo Characterization of Highly β(1)-Selective β-Adrenoceptor Partial Agonists |
title | Synthesis
and in Vitro and in Vivo Characterization
of Highly β(1)-Selective β-Adrenoceptor
Partial Agonists |
title_full | Synthesis
and in Vitro and in Vivo Characterization
of Highly β(1)-Selective β-Adrenoceptor
Partial Agonists |
title_fullStr | Synthesis
and in Vitro and in Vivo Characterization
of Highly β(1)-Selective β-Adrenoceptor
Partial Agonists |
title_full_unstemmed | Synthesis
and in Vitro and in Vivo Characterization
of Highly β(1)-Selective β-Adrenoceptor
Partial Agonists |
title_short | Synthesis
and in Vitro and in Vivo Characterization
of Highly β(1)-Selective β-Adrenoceptor
Partial Agonists |
title_sort | synthesis
and in vitro and in vivo characterization
of highly β(1)-selective β-adrenoceptor
partial agonists |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694353/ https://www.ncbi.nlm.nih.gov/pubmed/23614528 http://dx.doi.org/10.1021/jm400348g |
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