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

Sophia Diamant, Israel Agranat, Amiram Goldblum, Shmuel Cohen, Daphne Atlas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)491-498
Number of pages8
JournalBiochemical Pharmacology
Volume34
Issue number4
DOIs
StatePublished - 15 Feb 1985

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