Pigini M, Brasili L, Giannella M, Giardinà D, Gulini U, Quaglia W, Melchiorre C
Department of Chemical Sciences, University of Camerino, Italy.
J Med Chem. 1988 Dec;31(12):2300-4. doi: 10.1021/jm00120a009.
Several analogues of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzodioxa n (WB 4101, 1) were prepared and evaluated for their blocking activity on alpha 1- and alpha 2-adrenoreceptors in the isolated rat vas deferens. The results were compared with those obtained for 1 and benoxathian (2). It was shown that the two oxygens at positions 1 and 4 may have a different role in receptor binding. It seems that the oxygen at position 4 as such does not contribute to the binding while it is important in stabilizing an optimal conformation for drug-receptor interaction mechanism. On the other hand, the oxygen at position 1 might interact with a receptor polar pocket of reduced size by way of a donor-acceptor dipolar interaction. Furthermore, it was shown that replacement of the dehydrodioxane ring of 1 by a phenyl or a pyrrole nucleus causes a significant decrease in activity.
制备了几种2-[[[2-(2,6-二甲氧基苯氧基)乙基]氨基]甲基]-1,4-苯并二恶烷（WB 4101，1）的类似物，并评估了它们对离体大鼠输精管中α1和α2肾上腺素能受体的阻断活性。将结果与化合物1和贝诺沙硫（2）的结果进行了比较。结果表明，1位和4位的两个氧原子在受体结合中可能具有不同的作用。似乎4位的氧原子本身对结合没有贡献，而它对于稳定药物-受体相互作用机制的最佳构象很重要。另一方面，1位的氧原子可能通过供体-受体偶极相互作用与尺寸减小的受体极性口袋相互作用。此外，结果表明，用苯基或吡咯核取代化合物1的二氢二恶烷环会导致活性显著降低。
