WB4101-Related Compounds:  New, Subtype-Selective α1-Adrenoreceptor Antagonists (or Inverse Agonists?)

• Published in: Journal of medicinal chemistry 2006-11, Vol.49 (24), p.7140-7149
• Main Authors: Pallavicini, Marco, Budriesi, Roberta, Fumagalli, Laura, Ioan, Pierfranco, Chiarini, Alberto, Bolchi, Cristiano, Ugenti, Maria Paola, Colleoni, Simona, Gobbi, Marco, Valoti, Ermanno
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Catecholaminergic system; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060358r

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 (pA 2 10.68) and moderately selective α1D-AR antagonist and the hybrid (S)-8 is a potent (pA 2 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.