WB4101-related compounds: New, subtype-selective α1- adrenoreceptor antagonists (or inverse agonists?)

Marco Pallavicini, Roberta Budriesi, Laura Fumagalli, Pierfranco Ioan, Alberto Chiarini, Cristiano Bolchi, Maria Paola Ugenti, Simona Colleoni, Marco Gobbi, Ermanno Valoti

Research output: Contribution to journalArticlepeer-review


Our previous structure-affinity relationship study had considered the enantiomers of the naphthodioxane, tetrahydronaphthodioxane, and 2-methoxy-1-naphthoxy analogues (compounds 1, 3, and 2, respectively) of 2-(2,6-dimethoxyphenoxyethylaminomethyl)-1,4-benzodioxane, the well-known α1-adrenoceptor (α1-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for α1-AR subtypes and 5-HT1A receptor. Here, we extend investigations to antagonist activity enclosing new enantiomeric pairs, namely those of the methoxytetrahydronaphthoxy and methoxybiphenyloxy WB4101 analogues (4 and 5-7, respectively) and of a double-modified WB4101 derivative (8) resulting from hybridization between 2 and 3. We found that (S)-2 is a very potent (pA2 10.68) and moderately selective α1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 7.98) and highly selective α1A-AR antagonist. Both of these compounds and (S)-WB4101 seem to act as inverse agonists in a vascular model. The results, which generally validate the logic we followed in designing these eight compounds, are acceptably rationalized by comparative SAR analysis of binding and functional affinities.

Original languageEnglish
Pages (from-to)7140-7149
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number24
Publication statusPublished - Nov 30 2006

ASJC Scopus subject areas

  • Organic Chemistry


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