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  • 10058-F4 receptor br Introduction Glucagon is a peptide

    2021-09-09


    Introduction Glucagon is a peptide hormone that acts to increase blood glucose levels. The secretion of glucagon from the alpha 10058-F4 receptor of the islets of Langerhans in the pancreas is increased during fasting and prevents hypoglycemia. Glucagon increases glycogenolysis and gluconeogenesis and thereby promotes glucose production in the liver.3, 4, 5 In type 2 diabetes, hyperglucagonemia is associated with hyperglycemia, and elevated glucagon levels exacerbate the hyperglycemic condition by increasing hepatic glucose production.3, 6 Therefore, reduction of glucagon concentrations or inhibition of glucagon actions might be a logical therapeutic strategy for the treatment of diabetes. Glucagon acts on target tissues via the glucagon receptor (GCGR), which is a member of the seven-transmembrane G-protein coupled receptor superfamily.2, 7 Glucagon binding to the GCGR activates adenylyl cyclase and increases intracellular cyclic adenosine monophosphate (cAMP), resulting in the biological effects.8, 9, 10, 11 Inhibition of the GCGR by GCGR neutralizing antibodies, anti-sense oligonucleotides and/or peptide and small molecule GCGR antagonists have been shown to decrease hepatic glucose output and improve glucose tolerance in various diabetes models.12, 13, 14, 15, 16 To date, various small molecule GCGR antagonists such as BAY 27-9955, MK-0893, PF-06291874, LY-2409021, and LGD-6972, etc.17, 18, 19, 20 have been developed and evaluated as therapeutic agents for diabetes (Fig. 1). In this paper, we report a series of phenylpyrimidines as novel GCGR antagonists. We found that the compound named has therapeutic effects in a type 2 diabetic model.
    Results and discussion
    Conclusion A series of novel phenylpyrimidine derivatives were designed, synthesized, and evaluated as GCGR antagonists. Based on the inhibitory efficacy of glucagon-induced cAMP production in CHO-K1 GCGR Gs cells and glucagon-induced glucose production in mouse primary hepatocytes, we selected compounds 7a and 7f for further study. We next synthesized the two enantiomers of 7a and 7f, and then selected and for in vivo study based on their superior inhibitory effects on glucagon-induced glucose production and cAMP production. In addition, The GCGR antagonist showed good efficacy of glucagon signaling blockage and blood glucose lowering effect in a diabetic animal model. Our results suggest that the compound could be a potential glucose-lowering agent for treating type 2 diabetes.
    Experimental
    Author contributions
    Introduction Oxyntomodulin (OXM) is a 37 amino-acid peptide produced by the neuroendocrine L-cells of the ileum. It consists of the 29 amino acids of glucagon plus an octapeptide tail. So far, no specific OXM receptor has been identified. OXM does activate the glucagon receptor, though less potently than native glucagon due to the octapeptide tail. The same tail allows OXM to activate the GLP-1 receptor, but also less potently than native GLP-1 [1], [2], [3], [4]. Additionally, the octapeptide tail slows clearance of OXM from the circulation when compared to glucagon [5]. OXM is produced by the action of PCSK1 proprotein convertase subtilisin/kexin type 1 on the proglucagon peptide. OXM is co-secreted from the intestine with GLP-1 in response to nutrient intake. Like GLP-1, OXM is an incretin, directly causing insulin release from pancreatic islet cells. All current available obesity treatments – dietary, pharmacological and surgical – reduce food intake. However, the initial weight loss from the food intake reduction is associated with a fall in energy expenditure, which limits overall weight loss [6], [7], [8]. Conversely, states where energy expenditure is increased, such as thyrotoxicosis or cold exposure, are accompanied by a compensatory hyperphagia, which has a similar limiting effect on weight loss [9], [10]. Short-term studies suggest that administration of exogenous OXM can reduce body weight in humans [4], [5]. The efficacy of OXM, compared to other anti-obesity treatments, arises from its ability to both reduce food intake and increase energy expenditure. By affecting both sides of the energy balance equation, OXM offers a means of causing effective and sustainable weight loss.