Small molecule allosteric modulation of the glucagon-like peptide-1 receptor enhances the insulinotropic effect of oxyntomodulin

Molecular Pharmacology

Volumn 82, Issue 6, 2012, Pages 1066-1073

  Willard, Francis S ^a   Wootten, Denise ^b   Showalter, Aaron D ^a   Savage, Emilia E ^b   Ficorilli, James ^a   Farb, Thomas B ^a   Bokvist, Krister ^a   Alsina Fernandez, Jorge ^a   Furness, Sebastian G B ^b   Christopoulos, Arthur ^b   Sexton, Patrick M ^b   Sloop, Kyle W ^a  

^a ELI LILLY AND COMPANY   (United States)

^b MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

4 (3 BENZYLOXYPHENYL) 2 ETHYLSULFINYL 6 (TRIFLUOROMETHYL)PYRIMIDINE; CCAAT ENHANCER BINDING PROTEIN ALPHA; CYCLIC AMP; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; OXYNTOMODULIN; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; BINDING COMPETITION; CONTROLLED STUDY; DRUG POTENTIATION; IN VITRO STUDY; IN VIVO STUDY; INSULIN LIKE ACTIVITY; INSULIN RELEASE; INTRAVENOUS GLUCOSE TOLERANCE TEST; MALE; NONHUMAN; PRIORITY JOURNAL; RAT; SIGNAL TRANSDUCTION;

ANIMALS; CELL LINE; CHO CELLS; CRICETINAE; CYCLIC AMP; DIABETES MELLITUS, TYPE 2; DRUG SYNERGISM; GLUCAGON-LIKE PEPTIDE 1; GTP-BINDING PROTEINS; HEK293 CELLS; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; OXYNTOMODULIN; RECEPTORS, GLUCAGON; SIGNAL TRANSDUCTION;

EID: 84869842165     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.112.080432     Document Type: Article

References (41)

1. Aurelio L, Valant C, Flynn BL, Sexton PM, Christopoulos A, and Scammells PJ (2009) Allosteric modulators of the adenosine A1 receptor: synthesis and pharmacological evaluation of 4-substituted 2-amino-3-benzoylthiophenes. J Med Chem 52:4543-4547.
2. Avlani VA, McLoughlin DJ, Sexton PM, and Christopoulos A (2008) The impact of orthosteric radioligand depletion on the quantification of allosteric modulator interactions. J Pharmacol Exp Ther 325:927-934. (Pubitemid 351724323)
3. Baggio LL, Huang Q, Brown TJ, and Drucker DJ (2004) Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology 127:546-558. (Pubitemid 39091903)
4. Baldissera FG, Holst JJ, Knuhtsen S, Hilsted L, and Nielsen OV (1988) Oxyntomodulin (glicentin-(33- 69)): pharmacokinetics, binding to liver cell membranes, effects on isolated perfused pig pancreas, and secretion from isolated perfused lower small intestine of pigs. Regul Pept 21:151-166.
5. Bochkov YA and Palmenberg AC (2006) Translational efficiency of EMCV IRES in bicistronic vectors is dependent upon IRES sequence and gene location. Biotechniques 41:283-284, 286, 288 passim.
6. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD, and Exenatide-113 Clinical Study Group (2004) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27:2628-2635. (Pubitemid 39441462)
7. Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, and Bloom SR (2003) Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab 88:4696-4701. (Pubitemid 37357514)
8. Dakin CL, Small CJ, Batterham RL, Neary NM, Cohen MA, Patterson M, Ghatei MA, and Bloom SR (2004) Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology 145:2687-2695. (Pubitemid 38686215)
9. DeFronzo RA, Okerson T, Viswanathan P, Guan X, Holcombe JH, and MacConell L (2008) Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study. Curr Med Res Opin 24:2943-2952.
10. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, and Baron AD (2005) Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28:1092-1100. (Pubitemid 40616618)
11. 35S]guanosine-5′-O-(3- thio)triphosphate binding mediated by cholinergic muscarinic receptors in membranes from Chinese hamster ovary cells and rat striatum using an anti-G protein scintillation proximity assay. J Pharmacol Exp Ther 289:946-955.
12. Druce MR and Bloom SR (2006) Oxyntomodulin: a novel potential treatment for obesity. Treat Endocrinol 5:265-272. (Pubitemid 44497475)
13. Fehmann HC, Jiang J, Schweinfurth J, Wheeler MB, Boyd AE 3rd, and Göke B (1994) Stable expression of the rat GLP-I receptor in CHO cells: activation and binding characteristics utilizing GLP-I(7-36)-amide, oxyntomodulin, exendin-4, and exendin(9-39). Peptides 15:453-456. (Pubitemid 24223320)
14. Hansotia T, Maida A, Flock G, Yamada Y, Tsukiyama K, Seino Y, and Drucker DJ (2007) Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J Clin Invest 117:143-152. (Pubitemid 46048461)
15. Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, et al. (2005) Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther 78:675-688. (Pubitemid 41773643)
16. Holst JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87:1409-1439.
17. Institute of Laboratory Animal Resources (1996) Guide for the Care and Use of Laboratory Animals, 7th ed., Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, Washington, DC.
18. Jorgensen R, Martini L, Schwartz TW, and Elling CE (2005) Characterization of glucagon-like peptide-1 receptor β-arrestin 2 interaction: a high-affinity receptor phenotype. Mol Endocrinol 19:812-823. (Pubitemid 40349451)
19. Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, and Baron AD (2005) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 28:1083-1091. (Pubitemid 40616617)
20. Kervran A, Dubrasquet M, Blache P, Martinez J, and Bataille D (1990) Metabolic clearance rates of oxyntomodulin and glucagon in the rat: contribution of the kidney. Regul Pept 31:41-52. (Pubitemid 20354176)
21. Kim MK, Kim HD, Cheong YH, Yang EK, Choi SH, Shin CY, Jung HH, Kim EJ, Moon HS, Yang HS et al. (2010) 590-P Orally active small molecule GLP-1R agonist, DA-15864 increases insulin secretion in mice, in Proceedings of the 70th American Diabetes Association Scientific Sessions; 2010 June 25-29; Orlando, FL. American Diabetes Association, Alexandria, VA.
22. Knudsen LB, Kiel D, Teng M, Behrens C, Bhumralkar D, Kodra JT, Holst JJ, Jeppesen CB, Johnson MD, de Jong JC, et al. (2007) Small-molecule agonists for the glucagon-like peptide 1 receptor. Proc Natl Acad Sci USA 104:937-942. (Pubitemid 46154715)
23. Koole C, Wootten D, Simms J, Valant C, Sridhar R, Woodman OL, Miller LJ, Summers RJ, Christopoulos A, and Sexton PM (2010) Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner: implications for drug screening. Mol Pharmacol 78:456-465.
24. Lamont BJ, Li Y, Kwan E, Brown TJ, Gaisano H, and Drucker DJ (2012) Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice. J Clin Invest 122:388-402.
25. Le Quellec A, Kervran A, Blache P, Ciurana AJ, and Bataille D (1992) Oxyntomodulin-like immunoreactivity: diurnal profile of a new potential enterogastrone. J Clin Endocrinol Metab 74:1405-1409.
26. Leach K, Sexton PM, and Christopoulos A (2007) Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology. Trends Pharmacol Sci 28:382-389. (Pubitemid 47087967)
27. Maida A, Lovshin JA, Baggio LL, and Drucker DJ (2008) The glucagon-like peptide-1 receptor agonist oxyntomodulin enhances β-cell function but does not inhibit gastric emptying in mice. Endocrinology 149:5670-5678.
28. May LT, Leach K, Sexton PM, and Christopoulos A (2007) Allosteric modulation of G protein-coupled receptors. Annu Rev Pharmacol Toxicol 47:1-51. (Pubitemid 46277033)
29. Mojsov S, Heinrich G, Wilson IB, Ravazzola M, Orci L, and Habener JF (1986) Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing. J Biol Chem 261:11880-11889. (Pubitemid 17206117)
30. Moon HS, Yang JS, Kim MK, Kim JK, Lee JY, Kang SM, Kim HD, Shin CY, Cheong YH, Yang EK, et al. (2011), inventors; Dong-A Pharmaceutical Co., Ltd., assignee. Novel quinoxilane derivatives. World patent WO/2011/122815. 2011 June 10.
31. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP, and Sitagliptin Study 024 Group (2007) Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 9:194-205.
32. Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, Du X, Petrov A, Lassman ME, Jiang G, et al. (2009) Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58:2258-2266.
33. Santoprete A, Capitò E, Carrington PE, Pocai A, Finotto M, Langella A, Ingallinella P, Zytko K, Bufali S, Cianetti S, et al. (2011) DPP-IV-resistant, long-acting oxyntomodulin derivatives. J Pept Sci 17:270-280.
34. Schjoldager BT, Baldissera FG, Mortensen PE, Holst JJ, and Christiansen J (1988) Oxyntomodulin: a potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man. Eur J Clin Invest 18:499-503.
35. Siegel EG, Gallwitz B, Scharf G, Mentlein R, Morys-Wortmann C, Fölsch UR, Schrezenmeir J, Drescher K, and Schmidt WE (1999) Biological activity of GLP-1-analogues with N-terminal modifications. Regul Pept 79:93-102. (Pubitemid 29376393)
36. Sloop KW, Willard FS, Brenner MB, Ficorilli J, Valasek K, Showalter AD, Farb TB, Cao JX, Cox AL, Michael MD, et al. (2010) Novel small molecule glucagon-like peptide-1 receptor agonist stimulates insulin secretion in rodents and from human islets. Diabetes 59:3099-3107.
37. Teng M, Johnson MD, Thomas C, Kiel D, Lakis JN, Kercher T, Aytes S, Kostrowicki J, Bhumralkar D, Truesdale L, et al. (2007) Small molecule ago-allosteric modulators of the human glucagon-like peptide-1 (hGLP-1) receptor. Bioorg Med Chem Lett 17:5472-5478. (Pubitemid 47391264)
38. Willard FS, Bueno AB, and Sloop KW (2012) Small molecule drug discovery at the glucagon-like peptide-1 receptor. Exp Diabetes Res 2012:709893.
39. Wootten D, Savage EE, Valant C,May LT, Sloop KW, Ficorilli J, Showalter AD, Willard FS, Christopoulos A, and Sexton PM (2012) Allosteric modulation of endogenous metabolites as an avenue for drug discovery. Mol Pharmacol 82:281-290.
40. Wootten D, Simms J, Koole C, Woodman OL, Summers RJ, Christopoulos A, and Sexton PM (2011) Modulation of the glucagon-like peptide-1 receptor signaling by naturally occurring and synthetic flavonoids. J Pharmacol Exp Ther 336:540-550.
41. Zhu L, Tamvakopoulos C, Xie D, Dragovic J, Shen X, Fenyk-Melody JE, Schmidt K, Bagchi A, Griffin PR, Thornberry NA, et al. (2003) The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides: in vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1-38). J Biol Chem 278:22418-22423. (Pubitemid 36830293)