Abstract
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.
Highlights
Β-Adrenoceptor ligands comprise one of the most commonly used classes of drugs in clinical practice. β-Agonists have been used since the 1940s for their beneficial effects in respiratory disease[2,3] and β-antagonists (β-blockers) since the 1960s for the control of cardiovascular disease,[4,5] and both classes remain among the most commonly prescribed drugs today
− noradrenaline, dobutamine, xamoterol, and ICI 89406 all having relatively poor selectivity.[18−20] Here we have characterized the pharmacological properties of 1 and some novel derivatives and present the most selective β1-partial agonists reported to date
We investigated the potential clinical impact of this degree of partial agonism in a fully conscious rat model
Summary
Β-Adrenoceptor ligands comprise one of the most commonly used classes of drugs in clinical practice. β-Agonists have been used since the 1940s for their beneficial effects in respiratory disease[2,3] and β-antagonists (β-blockers) since the 1960s for the control of cardiovascular disease,[4,5] and both classes remain among the most commonly prescribed drugs today. One of the most highly β1-selective antagonists described to date was 1 (LK 204-545).[1] this ligand provided an ideal structural template to investigate further, there was no published synthetic route and, in reality, very little pharmacological data available for this compound. It was not commercially available and not readily accessible for pharmacological and other studies. We report a synthesis and the in vitro pharmacological characterization of 1 and several novel, highly β1-selective βadrenoceptor ligands, most of which display significant agonist activity
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