Metabolic and cardiovascular benefits and risks of 4-hydroxy guanabenz hydrochloride: α(2)-adrenoceptor and trace amine-associated receptor 1 ligand

BACKGROUND: α(2)-adrenoceptor ligands have been investigated as potential therapeutic agents for the treatment of obesity. Our previous studies have shown that guanabenz reduces the body weight of obese rats, presumably through its anorectic action. This demonstrates an additional beneficial effect on selected metabolic parameters, including glucose levels. The purpose of this present research was to determine the activity of guanabenz's metabolite—4-hydroxy guanabenz hydrochloride (4-OH-Guanabenz). METHODS: We performed in silico analyses, involving molecular docking to targets of specific interest as well as other potential biological targets. In vitro investigations were conducted to assess the selectivity profile of 4-OH-Guanabenz binding to α-adrenoceptors, along with intrinsic activity studies involving α(2)-adrenoceptors and trace amine-associated receptor 1 (TAAR(1)). Additionally, the effects of 4-OH-Guanabenz on the body weight of rats and selected metabolic parameters were evaluated using the diet-induced obesity model. Basic safety and pharmacokinetic parameters were also examined. RESULTS: 4-OH-guanabenz is a partial agonist of α(2A)-adrenoceptor. The calculated EC(50) value for it is 316.3 nM. It shows weak agonistic activity at TAAR(1) too. The EC(50) value for 4-OH-Guanabenz calculated after computer simulation is 330.6 µM. Its primary mode of action is peripheral. The penetration of 4-OH-Guanabenz into the brain is fast (t(max) = 15 min), however, with a low maximum concentration of 64.5 ng/g. 4-OH-Guanabenz administered ip at a dose of 5 mg/kg b.w. to rats fed a high-fat diet causes a significant decrease in body weight (approximately 14.8% compared to the baseline weight before treatment), reduces the number of calories consumed by rats, and decreases plasma glucose and triglyceride levels. CONCLUSIONS: The precise sequence of molecular events within the organism, linking the impact of 4-OH-Guanabenz on α(2A)-adrenoceptor and TAAR(1) with weight reduction and the amelioration of metabolic disturbances, remains an unresolved matter necessitating further investigation. Undoubtedly, the fact that 4-OH-Guanabenz is a metabolite of a well-known drug has considerable importance, which is beneficial from an economic point of view and towards its further development as a drug candidate. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-023-00518-9.