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) of2-(2,6-dimethoxyphenoxyethylaminomethyl)-1,4-benzodioxane, the well-known
1-adrenoceptor (
1-AR)antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivityprofile for
1-AR subtypes and 5-HT
1A receptor. Here, we extend investigations to antagonist activity enclosingnew enantiomeric pairs, namely those of the methoxytetrahydronaphthoxy and methoxybiphenyloxy WB4101analogues (
4 and
5-7, respectively) and of a double-modified WB4101 derivative (
8) resulting fromhybridization between
2 and
3. We found that (
S)-
2 is a very potent (p
A2 10.68) and moderately selective
1D-AR antagonist and the hybrid (
S)-
8 is a potent (p
A2 7.98) and highly selective
1A-AR antagonist. Bothof 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 rationalizedby comparative SAR analysis of binding and functional affinities.