title: Novel chiral isoxazole derivatives: synthesis and pharmacological characterization at human beta-adrenergic receptor subtypes.
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 beta(1)-, beta(2)-, and beta(3)-adrenergic receptors (beta-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 beta-ARs, stereoisomers (S,R)-7a-(S,R)-9a behaved as high-affinity ligands at beta(1)- and, particularly, at beta(2)-ARs (K(i) 2.82-66.7 nM). The K(i) values of isomers (R,R)-7b-(R,R)-9b at beta(1)- and beta(2)-subtypes were about 30-100 times higher than those of their (S,R)-7a-9a counterparts, indicating a sizable stereochemical effect. The affinity at beta(3)-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 beta-AR subtypes. The highest value of efficacy (75-90%) was observed at beta(2)-ARs, whereas all compounds behaved as partial agonists (30-60%) at the beta(3)-subtype. The lowest degree of efficacy (15-35%) was found at beta(1)-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].
authors.affiliation: Istituto di Chimica Farmaceutica e Tossicologica "Pietro Pratesi", Università degli Studi di Milano, Viale Abruzzi 42, 20131 Milano, Italy.
authors.forename: Clelia
authors.initials: C
authors.lastname: Dallanoce
authors.forename: Fabio
authors.initials: F
authors.lastname: Frigerio
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
authors.forename: Sandra
authors.initials: S
authors.lastname: Dorsch
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007202:Indicators and Reagents; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D011869:Radioligand Assay; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007202:Indicators and Reagents; D007555:Isoxazoles; D018343:Receptors, Adrenergic, beta-2; D000262:Adenylyl Cyclases