Synthesis of enantiopure Δ2-isoxazoline derivatives and evaluation of their affinity and efficacy profiles at human β-adrenergic receptor subtypes

Clelia Dallanoce, Giuseppe Meroni, Marco De Amici, Carsten Hoffmann, Karl Norbert Klotz, Carlo De Micheli

Research output: Contribution to journalArticle

Abstract

The new enantiomerically pure 3-substituted-Δ2-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 β1-, β2-, and β3-adrenergic receptor (β-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 β-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 Δ2-isoxazoline derivatives provided with a detectable binding affinity showed the overall profile of neutral antagonists at all three β-AR subtypes.

Original languageEnglish
Pages (from-to)4393-4401
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number13
DOIs
Publication statusPublished - Jul 1 2006

Keywords

  • Δ-Isoxazoline derivatives
  • Antagonist
  • Binding affinity
  • Efficacy
  • Human β-adrenergic receptor subtypes
  • Synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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