WB4101-Related Compounds: New, Subtype-Selective 1-Adrenoreceptor Antagonists (or Inverse Agonists?)
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- 作者：Marco Pallavicini ; Roberta Budriesi ; Laura Fumagalli ; Pierfranco Ioan ; Alberto Chiarini ; Cristiano Bolchi ; Maria Paola Ugenti ; Simona Colleoni ; Marco Gobbi ; Ermanno Valoti
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：November 30, 2006
- 年：2006
- 卷：49
- 期：24
- 页码：7140 - 7149
- 全文大小：152K
- 年卷期：v.49,no.24(November 30, 2006)
- ISSN：1520-4804
文摘
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-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 selective1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 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.
1-adrenoceptor (1-AR)antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivityprofile for 1-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 selective1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 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.