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Synthesis and in vitro and in vivo characterization of highly ?1-Selective ?-Adrenoceptor partial agonists

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 ?1-Selective ?-Adrenoceptor partial agonists Thumbnail


Professor of Drug Discovery and Respiratory Medicine

Peter M. Fischer

Professor of Molecular Pharmacology

Sheila M. Gardiner

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Professor of Medicinal Chemistry


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 β1-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),1 a selective β1-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1’s aromatic nitrile afforded 19, a ligand with similar β1-adrenoceptor selectivity and partial agonism (log KD of −7.75 and −5.15 as an antagonist of functional β1- and β2-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β1)). 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 β1- selectivity.

Journal Article Type Article
Acceptance Date Apr 1, 2013
Publication Date Apr 24, 2013
Deposit Date Sep 30, 2015
Publicly Available Date Sep 30, 2015
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 0022-2623
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 56
Issue 10
Public URL
Publisher URL


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