β-adrenergic activity and conformation of the antihypertensive specific α₂-agonist drug, guanabenz

In recent research a new series of specific drugs, one of which is guanabenz (GBZ, 2,6(di-chlorobenzyliden)-aminoguanidine)† has been introduced into the clinical treatment of centrally mediated hypertension. Guanabenz (GBZ) is considered to be among the most specific α₂-adrenergic agonists, acting similarly to clonidine by decreasing the sympathetic outflow from the brain to the peripheral circulatory system. In the present report we show that GBZ displays a significant affinity for β-adrenoceptors. In displacement studies of the iodinated β-antagonist [¹²⁵I]cyanopindolol (CYP) from turkey erythrocyte membranes, the dissociation constant of GBZ was 3.8 μM. Inhibition of the (-) epinephrine induced adenylate cyclase activity by GBZ is competitive, with an apparent dissociation constant of 30 μM. A similar value was obtained by studies of GBZ's effect on the (-)epinephrine-induced [³H]cAMP accumulation in intact turkey erythrocytes. In view of its unexpected affinity for β-adrenoceptors, we examined the three-dimensional structure of crystalline GBZ. In these studies substantial differences between clonidine and GBZ were observed, despite their strong structural resemblance. These dissimilarities (angle of rotation φ = 39.7° as compared to 76° in clonidine, and the rotational restriction of clonidine as compared to the greater mobility in rotation of GBZ) could explain the difference of specificity between these two compounds.