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首页> 外文期刊>Journal of Medicinal Chemistry >WB4101-related compounds: New, subtype-selective alpha(1)-adrenoreceptor antagonists (or inverse agonists?)
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WB4101-related compounds: New, subtype-selective alpha(1)-adrenoreceptor antagonists (or inverse agonists?)

机译：WB4101相关化合物：新型亚型选择性α（1）-肾上腺素受体拮抗剂（或反向激动剂？）

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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 alpha(1)-adrenoceptor (alpha(1)-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for alpha(1)-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 alpha(1D)-AR antagonist and the hybrid (S)-8 is a potent (pA(2) 7.98) and highly selective alpha(1A)-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.
机译：我们先前的结构亲和关系研究已经考虑了2-（2,6-二甲氧基苯氧基乙基氨基甲基）-1的萘二恶烷，四氢萘二恶烷和2-甲氧基-1-萘氧基类似物（分别为化合物1、3和2）的对映体， 4-苯并二恶烷，众所周知的alpha（1）-肾上腺素能受体（alpha（1）-AR）拮抗剂WB4101，表明此类修饰显着调节了alpha（1）-AR亚型和5-HT1A受体的亲和力和选择性。在这里，我们将研究范围扩展到封闭新对映体对的拮抗剂活性，即对甲氧基四氢萘氧基和甲氧基联苯氧基WB4101类似物（分别为4和5-7）和由2和3杂交产生的双修饰WB4101衍生物（8）。我们发现（S）-2是非常有效的（pA（2）10.68）和中等选择性的alpha（1D）-AR拮抗剂，而杂种（S）-8是有效的（pA（2）7.98）和高度选择性alpha（1A）-AR拮抗剂。这些化合物和（S）-WB4101似乎都在血管模型中起反向激动剂的作用。通过比较结合和功能亲和力的SAR分析，可以合理地合理化设计这八种化合物所遵循的逻辑结果。

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