Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Arylsulfonamides
نویسندگان
چکیده
The inhibition of insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3) by angiotenesin IV is known to improve memory and learning in rats. Screening 10 500 low-molecular-weight compounds in an enzyme inhibition assay with IRAP from Chinese Hamster Ovary (CHO) cells provided an arylsulfonamide (N-(3-(1H-tetrazol-5-yl)phenyl)-4-bromo-5-chlorothiophene-2-sulfonamide), comprising a tetrazole in the meta position of the aromatic ring, as a hit. Analogues of this hit were synthesized, and their inhibitory capacities were determined. A small structure-activity relationship study revealed that the sulfonamide function and the tetrazole ring are crucial for IRAP inhibition. The inhibitors exhibited a moderate inhibitory potency with an IC50=1.1±0.5 μm for the best inhibitor in the series. Further optimization of this new class of IRAP inhibitors is required to make them attractive as research tools and as potential cognitive enhancers.
منابع مشابه
Vasopressin is a physiological substrate for the insulin-regulated aminopeptidase IRAP.
Insulin-regulated aminopeptidase (IRAP) is a membrane aminopeptidase and is homologous to the placental leucine aminopeptidase, P-LAP. IRAP has a wide distribution but has been best characterized in adipocytes and myocytes. In these cells, IRAP colocalizes with the glucose transporter GLUT4 to intracellular vesicles and, like GLUT4, translocates from these vesicles to the cell surface in respon...
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The insulin-regulated membrane aminopeptidase (IRAP) was originally identified in fat and muscle cells as a major protein in intracellular vesicles that also harbor the insulin-responsive glucose transporter GLUT4. IRAP, like GLUT4, predominantly localizes to these intracellular vesicles under basal conditions. In response to insulin IRAP, like GLUT4, translocates to the plasma membrane. Purifi...
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