Novel chiral isoxazole derivatives: Synthesis and pharmacological characterization at human β-adrenergic receptor subtypes

Isoxazole derivative (±)-4 and the three pairs of stereoisomeric 3-bromo-isoxazolyl amino alcohols (S, R)-(−)-7a/(R, R)-(+)-7b, (S, R)-(−)-8a/(R, R)-(+)-8b, and (S, R)-(−)-9a/(R, R)-(+)-9b were synthesized and assayed for their affinity and efficacy at human β1-, β2-, and β3-adrenergic receptors (β-ARs) in membranes from Chinese hamster ovary (CHO) cells stably transfected with the respective receptor subtype. Whereas derivative (±)-4 did not bind at all three β-ARs, stereoisomers (S, R)-7a-(S, R)-9a behaved as high-affinity ligands at β1- and, particularly, at β2-ARs (Ki 2.82–66.7 nM). The Ki values of isomers (R, R)-7b-(R, R)-9b at β1- and β2-subtypes were about 30–100 times higher than those of their (S, R)-7a–9a counterparts, indicating a sizable stereochemical effect. The affinity at β3-ARs was negligible for all the investigated compounds. When submitted to a functional assay, the three stereoisomeric pairs showed a comparable pattern of efficacy at all three β-AR subtypes. The highest value of efficacy (75–90%) was observed at β2-ARs, whereas all compounds behaved as partial agonists (30–60%) at the β3-subtype. The lowest degree of efficacy (15–35%) was found at β1-ARs. The affinity/efficacy profile of the derivatives under study has been compared with that of the two model compounds, Broxaterol [(±)-1] and BRL 37344 [(±)-6].

A set of new enantiopure isoxazole derivatives has been prepared and tested for their affinity and efficacy at human β1-, β2-, and β3-adrenergic receptor subtypes.Figure optionsDownload as PowerPoint slide