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

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-HT_1A 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 α_1D-AR antagonist and the hybrid (S)-8 is a potent (pA₂ 7.98) and highly selective α_1A-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.