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  • The synthetic adipoR agonists AdipoRon and are

    2022-11-30

    The synthetic adipoR agonists, AdipoRon (1) and 112254 (2), are both detectable in human plasma [18]. However, with increasing knowledge about their metabolism [19], a method for detection from human urine is conceivable and would be preferred given the easier accessibility and greater frequency of collection in human doping controls. Here, we present our process for incorporating the detection of AdipoRon (1) and 112254 (2) into routine doping control analytical methods for urine and dried blood spots (DBS). For the detection from urine, both adipoR agonists and their hydroxylated (i.e., metabolized) forms (1–4, Fig. 1) were targeted using liquid chromatography-tandem mass spectrometry (LC-MS/MS). For detection from DBS, AdipoRon (1) and 112254 (2) were targeted using liquid chromatography-high-resolution/high-accuracy tandem mass ABT 702 dihydrochloride spectrometry with online solid phase extraction (DBS online-SPE LC-HR-MS/MS).
    Experimental
    Results and discussion
    Conclusions AdipoR agonists are novel pharmacologically active compounds being used for the treatment of ABT 702 dihydrochloride type 2. These compounds also act as exercise mimetics, which activate enzymatic pathways that lead to increased mitochondrial content in muscle cells. Such effects can increase athletic performance making these compounds candidates for abuse by competitive athletes. Preventive anti-doping research is important in order to incorporate newly identified performance enhancing drugs into established initial testing protocols. In this study, AdipoRon (1), 112254 (2) and their respective metabolites (3 and 4) were introduced into a routinely employed LC-MS/MS doping control method for human urine. Additionally, the detection of adipoR agonists 1 and 2 from DBS using an automated DBS-onlineSPE-LC-HRMS-system was developed. After method validation, the detection of adipoR agonists, AdipoRon and 112254, and their metabolites was found to be fit-for-purpose. Both methods are planned to be included into future routine doping control screening analysis.
    Acknowledgements The study was supported by Antidoping Switzerland (Berne, Switzerland), the Federal Ministry of the Interior of the Federal Republic of Germany Bonn, Germany), and the Manfred-Donike-Institute for Doping Analysis (Cologne, Germany).
    The anti-diabetic actions of adiponectin Animal studies have been pivotal in providing evidence clarifying the role and mechanism of action of adiponectin and its receptors. Mouse models of increased insulin sensitivity such as the heterozygous peroxisome proliferator-activated receptor (PPAR)γ deficient mice have been used to screen for molecules secreted by white adipose tissue (WAT). Results demonstrate that the increased expression of adiponectin seen in these mice is associated with increased insulin sensitivity. Additional knowledge regarding the role adiponectin plays in glucose homeostasis was gained following an investigation into the effect of increasing the expression of adiponectin in insulin resistant mice (KKAy mice: KK mice overexpressing the agouti protein). A high-fat diet (HFD) was fed to KKAy mice, which resulted in decreased plasma adiponectin levels. The addition of adiponectin to these adiponectin-low mice resulted in significant improvement in the insulin resistance and hypertriglyceridemia, which they had developed in response to the HFD. Therefore adiponectin was recognized as an insulin-sensitizing adipokine [1]. An acute increase in the level of circulating adiponectin was also shown to trigger a transient decrease in basal glucose. This decrease in glucose levels, seen in both wild-type and type-2 diabetic mice, was associated with a reduction in hepatic gluconeogenic enzymes. Researchers proposed that adiponectin inhibits endogenous glucose production by sensitizing the body to insulin [2,3]. These findings were supported by evidence showing that a product of adiponectin increases fatty-acid oxidation in muscle, decreases plasma glucose, and causes weight loss in mice [4].