Interaction of clonidine, its methylene-bridged analog, St 1913, and the benzylic hydroxyl-substituted derivative, St 1965, with alpha 1- and alpha 2-adrenoreceptors.

The effects of benzylic hydroxyl substitution on the activity of a close structural analog of clonidine was assessed at alpha 1- and alpha 2-adrenoreceptors both in vitro and in vivo in order to uncover possible differences that this substitution may have on the effects of imidazolines and phenethylamines at adrenoreceptors. In all test systems, the presence of the benzylic hydroxyl group was associated with a consistent and marked decrease in activity. These findings are in agreement with our previous studies with imidazolines having different pharmacological profiles and different physicochemical properties than the clonidine derivatives reported herein. We conclude, therefore, that the deleterious effects of the benzylic hydroxyl group is ubiquitous among imidazolines and, more importantly, is in marked contrast to the 100-1000 fold enhancement in activity that the benzylic hydroxyl substituent (i.e. beta-hydroxyl group) produces for the phenethylamines. The results support the concept that imidazolines and phenethylamines may interact differently with alpha-adrenoreceptors.