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].

Novel chiral isoxazole derivatives: synthesis and pharmacological characterization at human b-adrenergic receptor subtypes / C. Dallanoce, F. Frigerio, M. De Amici, S. Dorsch, K.N. Klotz, C. De Micheli. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 15:7(2007), pp. 2533-2543.

Novel chiral isoxazole derivatives: synthesis and pharmacological characterization at human b-adrenergic receptor subtypes

C. Dallanoce;F. Frigerio
Secondo
;
M. De Amici;C. De Micheli
Ultimo
2007

Abstract

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].
Binding affinity; Efficacy; Human β-adrenergic receptor subtypes; Hybrid compounds; Isoxazole derivatives; Synthesis
Settore CHIM/08 - Chimica Farmaceutica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/35028
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