Differential binding of guanabenz and its metabolites to cerebral α₂‐receptors: The basis for a radioligand assay specific for the drug

Abstract

Guanabenz (E-2,6-dichlorobenzylideneaminoguanidine acetate, Wy-8678) and its identified metabolites were tested for their ability to displace [3H]clonidine from the cerebral a, -receptors of rat and dog. The Ki' s for inhibition of [3H]clonidine binding to rat membranes were 1.97, 0.96, 14.0, and 108 nM for clonidine, guanabenz, p-hydroxyguanabenz, and the Z-isomer of guanabenz, respectively. The other metabolites at concentrations of 10,000 nM did not displace [3H]clonidine. Scatchard analysis indicated single populations of binding sites with KD' s of 2.37 and 2.39 nM and Bmax's of 5.39 and 5.12 pmollg for rat and dog preparations, respectively. Hill analysis yielded coefficients approximating unity, indicating a lack of cooperativity in binding. The high affinity of guanabenz relative to that of its metabolites for the a,-receptor provided the basis for the development of an assay capable of discriminating guanabenz from its weakly hypotensive (p-hydroxyguanabenz and the Zisomer of guanabenz) and pharmacologically inactive (2-6,dichlorobenzyl alcohol,2,6-dichlorobenzaldehyde, 2,6-dichlorobenzaldehyde azine,2,6-dichlorobenzaldehyde sernicarbizone, creatinine adduct of 2,6-dichlorobenzaldehyde, and an isomer of the creatinine adduct) metabolites. Antihypertensive agents with different mechanisms of action such as indoramin, prazosin, debrisoquine, and bethanidine bound little, if at all, and thus will not interfere with the assay of guanabenz.

Microsomal Catalyzed N-Hydroxylation of Guanabenz and Reduction of the N-Hydroxylated Metabolite: Characterization of the Two Reactions and Genotoxic Potential of Guanoxabenz1

“…Even so, guanoxabenz most probably serves to a large extent as a prodrug of guanabenz, although the affinity of guanoxabenz to various subtypes of R 2 -adrenoreceptors has been demonstrated (20). It should be emphasized, however, that in comparison to guanabenz an approximately 70-fold lower affinity of guanoxabenz to rat cerebral R 2 -receptors has been reported (21). Recent work has principally implicated the central imidazoline receptors as being responsible for the blood pressure lowering activity of guanabenz (22,23) while the affinity of guanoxabenz for imidazoline receptors has not yet been investigated.…”

Solvatomorphism in (E)-2-(2,6-dichloro-4-hydroxybenzylidene)hydrazinecarboximidamide

“…Like polymorphism, solvatomorphism is also commonly observed in organics and is of great significance in pharmaceuticals and materials. (E)-2-(2,6-Dichloro-4-hydroxybenzylidene)hydrazinecarboximidamide, (1), is a metabolite of gaunabenz, an antiprion drug for the treatment of neurodegenerative disorders in mammals and also a potent tranquilizer used to sedate horses (Fluck et al, 1983). In this report, we describe three crystal structures of (1) which include two solvates, (I) and (II), and one acetate salt, (III) ( Fig.…”

Metabolic and cardiovascular benefits and risks of 4-hydroxy guanabenz hydrochloride: α2-adrenoceptor and trace amine-associated receptor 1 ligand

“…4-Hydroxy guanabenz (4-OH-Guanabenz) is a metabolite of guanabenz, which also possesses an affinity for the α 2 -adrenoceptor [ 22 ]. However, to date, the studies involving this compound are limited.…”