Target Validation Information
Target ID T20331
Target Name Neuropeptide Y receptor 5
Target Type
Research
Drug Potency against Target AR-129330 Drug Info IC50 = 2700 nM [527629]
FR-230481 Drug Info IC50 = 0.54 nM [526277]
NPY5RA-972 Drug Info IC50 = 3 nM [553205]
FR-233118 Drug Info IC50 = 0.7 nM [526277]
2,4,4-triphenylimidazoline Drug Info IC50 = 54 nM [529977]
FR-73966 Drug Info IC50 = 53 nM [526277]
FR-226928 Drug Info IC50 = 16 nM [526277]
CGP71683A Drug Info IC50 = 1.4 nM [552749]
Action against Disease Model CGP71683A CGP71683A alone induced cell death in a time- and dose-dependent manner in Y5R-expressing cells. The stimulation of MDA MB-231 cell migration by NPY is inhibited by CGP71683A [553033] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations We hypothesized that NPY in islets tonically suppresses insulin secretion and the reduction of islet NPY increases insulin secretion. To address the hypothesis, islet function of NPY-deficient mice was analyzed. Although there was little change in glucose homeostasis in vivo, pancreatic islets from NPY-deficient mice had higher basal insulin secretion (1.5 times), glucose-stimulated insulin secretion (1.5 times), and islet mass (1.7 times), compared with wild-type mouse. Next we sought to determine whether the expression of NPY and Y(1) receptor in islets was altered in hyperinsulinemia associated with obesity. Islets from C57BL/6J mice on a high-fat diet had 1.9 times higher basal insulin secretion and 2.4 times higher glucose-stimulated insulin secretion than control mice, indicating islet adaptation to obesity. Expression of NPY and Y(1) receptor mRNA levels was decreased by 70 and 64%, respectively, in high-fat diet islets, compared with controls. NPY and Y(1) receptor in islets were also reduced by 91 and 80%, respectively, in leptin-deficient ob/ob mice that showed marked hyperinsulinemia. Together these results suggest that endogenous NPY tonically inhibits insulin secretion from islets and a reduction of islet NPY may serve as one of the mechanisms to increase insulin secretion when islets compensate for insulin resistance associated with obesity [553033]
References
Ref 553033Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line. Mol Cancer Res. 2010 Apr;8(4):604-14. doi: 10.1158/1541-7786.MCR-09-0301. Epub 2010 Mar 23.
Ref 527629Bioorg Med Chem Lett. 2005 Sep 1;15(17):3853-6.Lead optimization of 4-(dimethylamino)quinazolines, potent and selective antagonists for the melanin-concentrating hormone receptor 1.
Ref 526277Bioorg Med Chem Lett. 2002 Mar 11;12(5):799-802.Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 3: 7-methoxy-1-hydroxy-1-substituted tetraline derivatives.
Ref 553205Binding and cAMP studies of melanotropin peptides with the cloned human peripheral melanocortin receptor, hMC1R. Biochem Biophys Res Commun. 1994 Nov 15;204(3):1137-42.
Ref 526277Bioorg Med Chem Lett. 2002 Mar 11;12(5):799-802.Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 3: 7-methoxy-1-hydroxy-1-substituted tetraline derivatives.
Ref 529977Bioorg Med Chem Lett. 2009 Mar 15;19(6):1670-4. Epub 2009 Feb 4.Discovery of substituted 2,4,4-triarylimidazoline derivatives as potent and selective neuropeptide Y Y5 receptor antagonists.
Ref 526277Bioorg Med Chem Lett. 2002 Mar 11;12(5):799-802.Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 3: 7-methoxy-1-hydroxy-1-substituted tetraline derivatives.
Ref 526277Bioorg Med Chem Lett. 2002 Mar 11;12(5):799-802.Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 3: 7-methoxy-1-hydroxy-1-substituted tetraline derivatives.
Ref 552749NPY Y1 and Y5 receptor selective antagonists as anti-obesity drugs. Curr Top Med Chem. 2007;7(17):1721-33.

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