Synthesis of enantiopure Delta2-isoxazoline derivatives and evaluation of their affinity and efficacy profiles at human beta-adrenergic receptor subtypes.
The new enantiomerically pure 3-substituted-Delta(2)-isoxazolin-5-yl-ethanolamines (+)-6a/(-)-6b, (-)-6a/(+)-6b, and (+)-7a/(-)-7b, prepared via a 1,3-dipolar cycloaddition-based approach, were tested for their affinity at human beta(1)-, beta(2)-, and beta(3)-adrenergic receptor (beta-AR) subtypes stably expressed in CHO cells. The corresponding 3-isopropenyl derivatives (+)-5a/(-)-5b, (-)-5a/(+)-5b, and some isoxazole analogs were also tested. The binding affinities at the beta-ARs of the isoxazolinyl amino alcohols were significantly lower than those of the corresponding isoxazole derivatives. A stereochemical effect was observed, since the process of molecular recognition is predominantly controlled by the (S)-configuration of the stereogenic center located at the 5 position of the heterocycle rather than by that of the stereocenter carrying the secondary alcohol group. On the contrary, the stereochemical features marginally affected the efficacy response; as a matter of fact, functional tests carried out on Delta(2)-isoxazoline derivatives provided with a detectable binding affinity showed the overall profile of neutral antagonists at all three beta-AR subtypes.
Dallanoce
Clelia
C
Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Milano, Italy.
Meroni
Giuseppe
G
De Amici
Marco
M
Hoffmann
Carsten
C
Klotz
Karl-Norbert
KN
De Micheli
Carlo
C
D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D007555:Isoxazoles; D011943:Receptors, Adrenergic, beta