WB4101-related compounds: new, subtype-selective alpha1-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 alpha1-adrenoceptor (alpha1-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for alpha1-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 alpha1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 7.98) and highly selective alpha1A-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.

Citation

Marco Pallavicini, Roberta Budriesi, Laura Fumagalli, Pierfranco Ioan, Alberto Chiarini, Cristiano Bolchi, Maria Paola Ugenti, Simona Colleoni, Marco Gobbi, Ermanno Valoti. WB4101-related compounds: new, subtype-selective alpha1-adrenoreceptor antagonists (or inverse agonists?). Journal of medicinal chemistry. 2006 Nov 30;49(24):7140-9

Mesh Tags

Substances

PMID: 17125266

search → result