Structure-Activity Relationships in 1,4-Benzodioxane Related Compounds. Investigation on the Role of the Dehydrodioxane Ring on alpha1-Adrenoreceptor Blocking Activity.

Several analogues of 2 4 [ [2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-l,4-benzodiox(aWn B 4101, 1) were preparedand evaluated for their blocking activity on al- and az-adrenoreceptors in the isolated rat vas deferens. The resultswere compared with those obtained for 1 and benoxathian (2). It was shown that the two oxygens at positions 1and 4 may have a different role in receptor binding. It seems that the oxygen at position 4 as such does not contributeto 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 ofa donor-acceptor dipolar interaction. Furthermore, it was shown that replacement of the dehydrodioxane ring of1 by a phenyl or a pyrrole nucleus causes a significant decrease in activity.