The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis

ObjectiveSimultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs – and thus inducing cardiovascular complications – are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2-and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models.MethodsIn the developmental phase, we assessed the impact of ATR-127's on cAMP accumulation in relation to the non-selective β-AR agonist isoprenaline across various rodent β-AR subtypes, including neonatal rat cardiomyocytes. Following these experiments, L6 muscle cells were stimulated with ATR-127 to assess the impact on GLUT4-mediated glucose uptake and intramyocellular cAMP accumulation. Additionally, in vitro, and in vivo assessments are conducted to measure ATR-127's effects on BAT glucose uptake and thermogenesis. Finally, diet-induced obese mice were treated with 5 mg/kg ATR-127 for 21 days to investigate the effects on glucose homeostasis, body weight, fat mass, skeletal muscle glucose uptake, BAT thermogenesis and hepatic steatosis.ResultsExposure of L6 muscle cells to ATR-127 robustly enhanced GLUT4-mediated glucose uptake despite low intramyocellular cAMP accumulation. Similarly, ATR-127 markedly increased BAT glucose uptake and thermogenesis both in vitro and in vivo. Prolonged treatment of diet-induced obese mice with ATR-127 dramatically improved glucose homeostasis, an effect accompanied by decreases in body weight and fat mass. These effects were paralleled by an enhanced skeletal muscle glucose uptake, BAT thermogenesis, and improvements in hepatic steatosis.ConclusionsOur results demonstrate that ATR-127 is a highly effective, novel β2- and β3-ARs agonist holding great therapeutic promise for the treatment of obesity and its comorbidities, whilst potentially limiting cardiovascular complications. As such, the therapeutic effects of ATR-127 should be investigated in more detail in clinical studies

Diarilēteru sintēze c-h aktivācijas ceļā

Iegūti jauna tipa platīna kompleksi. Pārbaudīta iegūto kompleksu reaģētspēja reducējošās eliminēšanas reakcijā

Pt(IV) Complexes: Synthesis and Reductive Elimination

This paper reports synthesis of novel platinum complexes. These structures would potentialy lead to synthesis of diaryl ether

Synthesis and Oxidation of Aryloxo Palladium Complexes of the Type [Pd(N-N)(Ar)(OAr')]

This paper reports synthesis of novel palladium complexes. These structures would potentialy lead to synthesis of diaryl ether

Palladium(II) Hydrides as Catalysts in Suzuki-Miyaura Reaction

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Catalytic Direct Acetoxylation of Indoles

3-Acetoxyindole-2-carboxylates could be readily synthesized in a Pd(OAc)2- or PtCl2-catalyzed direct C-3 acetoxylation of indole-2-carboxylates using PhI(OAc)2 as a terminal oxidant

Diazonamide Synthetic Studies. Reactivity of N-Unsubstituted Benzofuro[2,3-B]Indolines

Benzofuro[2,3-b]indolines undergo ring opening in the presence of base to generate 3H-indolines. The latter can rearrange into 3-arylindoles through an intramol. transfer of the methoxycarbonyl moiety from quaternary carbon to oxygen of phenol. The intermediate 3H-indolines can be isolated upon DMAP-catalyzed O-acylation of the phenol moiety with Boc2O

Preparation of 3-(Oxazol-5-Yl)Indolyl-4-Boronate in Synthesis of Diazonamide A

An Efficient approach towards building block of Diazonamide A is describe

Stereoselective Synthesis of the Diazonamide a Macrocyclic Core

Stereoselective synthesis of the right-hand heteroarom. macrocycle of diazonamide A features C16-C18 bond formation in the Suzuki-Miyaura cross-coupling and atropodiastereoselective Dieckmann-type macrocyclization as key steps. The Suzuki-Miyaura cross-coupling gave the best yields when it was catalyzed by a palladium-dioxygen complex

Stereoselective Synthesis of the Diazonamide A Macrocyclic Core

Stereoselective synthesis of the right-hand heteroaromatic macrocycle of diazonamide A features C16–C18 bond formation in the Suzuki–Miyaura cross-coupling and atropodiastereoselective Dieckmann-type macrocyclization as key steps. The Suzuki–Miyaura cross-coupling gave the best yields when it was catalyzed by a palladium–dioxygen complex