Preliminary Evidence of the Potent and Selective Adenosine A2B Receptor Antagonist PSB-603 in Reducing Obesity and Some of Its Associated Metabolic Disorders in Mice

Abstract

The adenosine A2A and A2B receptors are promising therapeutic targets in the treatment of obesity and diabetes since the agonists and antagonists of these receptors have the potential to positively affect metabolic disorders. The present study investigated the link between body weight reduction, glucose homeostasis, and anti-inflammatory activity induced by a highly potent and specific adenosine A2B receptor antagonist, compound PSB-603. Mice were fed a high-fat diet for 14 weeks, and after 12 weeks, they were treated for 14 days intraperitoneally with the test compound. The A1/A2A/A2B receptor antagonist theophylline was used as a reference. Following two weeks of treatment, different biochemical parameters were determined, including total cholesterol, triglycerides, glucose, TNF-α, and IL-6 blood levels, as well as glucose and insulin tolerance. To avoid false positive results, mouse locomotor and spontaneous activities were assessed. Both theophylline and PSB-603 significantly reduced body weight in obese mice. Both compounds had no effects on glucose levels in the obese state; however, PSB-603, contrary to theophylline, significantly reduced triglycerides and total cholesterol blood levels. Thus, our observations showed that selective A2B adenosine receptor blockade has a more favourable effect on the lipid profile than nonselective inhibition.

Recent Developments in Protein Lactylation in PTSD and CVD: Novel Strategies and Targets

“…Adenosine, acting via the A2B receptor (A2BR), upregulates HIF-1α even in the absence of hypoxia, suggesting a druggable PTSD and CVD target [ 202 ]. Indeed, PSB-603, an A2BR antagonist, has been found to reduce both obesity and the effects of aging, indicating potential beneficial effects for ECs senescence, EVA, and thymic involution, associated with PTSD and CVD [ 203 , 204 ]. In addition, A2BRs modulate EPO synthesis, a hormone endowed with antidepressant and anxiolytic properties of its own [ 205 , 206 ].…”

Multimodal Strategies to Fight Obesity: Research on Tailored Therapies Based on Natural and Synthetic Compounds for Prevention, Management and Treatment

“…However, its side effects, such as hyperactivity and heart rhythm disturbances, represent a problem. Kotańska et al [ 43 ] compared the effect of theophylline with that of PSB-603, a specific adenosine A2B receptor antagonist, on high-fat/high-sugar diet-fed mice and demonstrated that both the A2B receptor antagonists significantly lowered the body weights of the mice. However, only PSB-603 was also capable of reducing triglycerides and total cholesterol blood levels in mice, thus suggesting that blocking A2A with a specific antagonist has stronger effects on lipid reduction than non-selective inhibition.…”