| Abstract
| - 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 α1-adrenoceptor (α1-AR)antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivityprofile for α1-AR subtypes and 5-HT1A 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 (pA2 10.68) and moderately selectiveα1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 7.98) and highly selective α1A-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.
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