Guanabenz Degradation Products and Stability Assay

Jiang

et al. 2023

Chem. Res. Toxicol.

Overdose of acetaminophen, a widely used antipyretic and analgesic drug, is one of the leading causes of drug-induced acute liver injury in the United States and worldwide. Phase-I metabolism of acetaminophen generates the toxic N-acetyl-p-benzoquinone imine (NAPQI) intermediate. Reactions of NAPQI with a wide range of biomolecules cause increased oxidative stress, endoplasmic reticulum (ER) stress, inflammation, and mitochondrial dysfunction, some of the cellular events contributing toward liver toxicity. Previously, we evaluated the potential of an FDA-approved, ER stress-modulating antihypertensive drug, Wytensin (trans-guanabenz, E-GA), as an antidote for acetaminophen hepatotoxicity. E-GA prevented elevation of the liver enzyme alanine aminotransferase (ALT), even when administered up to 6 h after acetaminophen overdose, and exhibited synergistic analgesic interactions. However, the commercially available guanabenz exists solely as a trans-isomer and suffers from sedative side effects resulting from the inhibition of central α2A-adrenergic receptors in locus coeruleus. Here, we studied the utility of the relatively unexplored cis-isomer of guanabenz as a treatment option for acetaminophen-induced liver toxicity. cis(Z)-Guanabenz acetate (Z-GA) lacks interaction with α2A-adrenoreceptors and is thus devoid of sedative, blood-pressure-lowering side effects of E-GA. Treatment of mice with Z-GA (10 mg/kg) before acetaminophen overdose and up to 6 h post APAP administration prevented liver injury and suppressed the elevation of serum ALT levels. Mechanistically, hepatoprotective effects of both isomers are similar and partly attributed to attenuation of the ER stress and oxidative stress in the liver. The results of this study suggest that Z-GA may be a safer, effective antidote for the clinical management of acute liver injury resulting from acetaminophen overdose. It also raises a tantalizing possibility of a prophylactic combination of the geometric isomer of the approved drug guanabenz with acetaminophen in a clinical setting.

Section: Discussionmentioning

confidence: 95%

“…The geometric isomer of the clinically used trans -guanabenz, viz. E -GA, was previously isolated and characterized as a photolytic degradation product during stability experiments .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Geometric Isomer of Guanabenz Confers Hepatoprotection to a Murine Model of Acetaminophen Toxicity

Jiang

et al. 2023

Chem. Res. Toxicol.

Drug Development Research

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

Fluck¹,

Homon²,

Knowles³

et al. 1983

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.

Journal of Heterocyclic Chem

NMR spectroscopic investigations with isatin guanylhydrazones

Hölzer

Györgydeák

1996