Small-molecule agonists for the glucagon-like peptide 1 receptor

The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists.

[1]  W. Greenlee,et al.  Non-peptide Angiotensin Agonist , 1995, The Journal of Biological Chemistry.

[2]  J G Gleason,et al.  A small, nonpeptidyl mimic of granulocyte-colony-stimulating factor [see commetns]. , 1998, Science.

[3]  F. Gasparini,et al.  The Non-competitive Antagonists 2-Methyl-6-(phenylethynyl)pyridine and 7-Hydroxyiminocyclopropan[b]chromen-1a-carboxylic Acid Ethyl Ester Interact with Overlapping Binding Pockets in the Transmembrane Region of Group I Metabotropic Glutamate Receptors* , 2000, The Journal of Biological Chemistry.

[4]  D. Drucker,et al.  Cardiac function in mice lacking the glucagon-like peptide-1 receptor. , 2003, Endocrinology.

[5]  P. Rorsman,et al.  Imidazoline NNC77-0074 stimulates insulin secretion and inhibits glucagon release by control of Ca2+-dependent exocytosis in pancreatic α- and β-cells , 2003 .

[6]  T. Schwartz,et al.  Metal Ion-mediated Agonism and Agonist Enhancement in Melanocortin MC1 and MC4 Receptors* , 2002, The Journal of Biological Chemistry.

[7]  A. Kuki,et al.  Identification of alkylidene hydrazides as glucagon receptor antagonists. , 2001, Journal of medicinal chemistry.

[8]  Robert A. Rizza,et al.  β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes , 2003, Diabetes.

[9]  Mei Bai,et al.  Dimerization of G-protein-coupled receptors: roles in signal transduction. , 2004, Cellular signalling.

[10]  M. Maccoss,et al.  Characterization of a Novel, Non-peptidyl Antagonist of the Human Glucagon Receptor* , 1999, The Journal of Biological Chemistry.

[11]  B. Wulff,et al.  Different domains of the glucagon and glucagon‐like peptide‐1 receptors provide the critical determinants of ligand selectivity , 2003, British journal of pharmacology.

[12]  B. Thorens.  Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[13]  S. Rees,et al.  GPCR drug discovery through the exploitation of allosteric drug binding sites. , 2002, Receptors & channels.

[14]  W. Banks,et al.  Glucagon-like peptide-1 receptor is involved in learning and neuroprotection , 2003, Nature Medicine.

[15]  J. Luengo,et al.  Hydrazinonaphthalene and azonaphthalene thrombopoietin mimics are nonpeptidyl promoters of megakaryocytopoiesis. , 2001, Journal of medicinal chemistry.

[16]  C. Stidsen,et al.  Discovery of a Novel Non-Peptide Somatostatin Agonist with SST4 Selectivity , 1998 .

[17]  J. Holst,et al.  Both Subcutaneously and Intravenously Administered Glucagon-Like Peptide I Are Rapidly Degraded From the NH2-Terminus in Type II Diabetic Patients and in Healthy Subjects , 1995, Diabetes.

[18]  T. Schwartz,et al.  Nonpeptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist and as positive or negative allosteric modulators of ghrelin signaling. , 2005, Molecular endocrinology.

[19]  J. Holst,et al.  Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects. , 2003, The Journal of clinical endocrinology and metabolism.

[20]  R. DeFronzo,et al.  Pathogenesis of NIDDM: A Balanced Overview , 1992, Diabetes Care.

[21]  J. Sturis,et al.  Alterations in pulsatile insulin secretion in the Zucker diabetic fatty rat. , 1994, The American journal of physiology.

[22]  J. Holst,et al.  Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in Type 2 (non-insulin-dependent) diabetic patients , 1993, Diabetologia.

[23]  P. Damsbo,et al.  Glucagon-like peptide-1 infusion must be maintained for 24 h/day to obtain acceptable glycemia in type 2 diabetic patients who are poorly controlled on sulphonylurea treatment. , 2001, Diabetes care.

[24]  P Ghanouni,et al.  Functionally Different Agonists Induce Distinct Conformations in the G Protein Coupling Domain of the β2Adrenergic Receptor* , 2001, The Journal of Biological Chemistry.

[25]  J. Habener,et al.  The glucagon-like peptides. , 1999, Endocrine reviews.

[26]  S. Lazareno,et al.  Allosteric Regulation of Binding and Function at GCPRS , 2004, Medicinal Chemistry Research.

[27]  L. Prézeau,et al.  The Heptahelical Domain of GABAB2 Is Activated Directly by CGP7930, a Positive Allosteric Modulator of the GABAB Receptor* , 2004, Journal of Biological Chemistry.

[28]  K. Nakahara,et al.  Nonpeptide mimic of bradykinin with long-acting properties at the bradykinin B2 receptor. , 1997, Molecular pharmacology.

[29]  L. Orci,et al.  THE ESSENTIAL ROLE OF GLUCAGON IN THE PATHOGENESIS OF DIABETES MELLITUS , 1975, The Lancet.

[30]  Jeppe Sturis,et al.  One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. , 2004, Diabetes.

[31]  J. Holst,et al.  Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study , 2002, The Lancet.

[32]  G. Tsujimoto,et al.  Characterization of a novel nonpeptide vasopressin V2‐agonist, OPC‐51803, in cells transfected human vasopressin receptor subtypes , 2000, British journal of pharmacology.

[33]  R G Smith,et al.  Discovery of a small molecule insulin mimetic with antidiabetic activity in mice. , 1999, Science.

[34]  P. Rorsman,et al.  Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes. , 1998, Diabetes.

[35]  T. Schwartz,et al.  Differentiation between binding sites for angiotensin II and nonpeptide antagonists on the angiotensin II type 1 receptors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[36]  T. Kenakin.  Principles: receptor theory in pharmacology. , 2004, Trends in pharmacological sciences.

[37]  L. Bačáková,et al.  Activation of muscarinic acetylcholine receptors via their allosteric binding sites. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. A. Jensen,et al.  Allosteric modulation of G-protein coupled receptors. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[39]  S. Pong,et al.  A nonpeptidyl growth hormone secretagogue. , 1993, Science.

[40]  S. Betz,et al.  Single amino acid residue determinants of non-peptide antagonist binding to the corticotropin-releasing factor1 (CRF1) receptor. , 2006, Biochemical pharmacology.

[41]  J. Levy,et al.  U.K. Prospective Diabetes Study 16: Overview of 6 Years' Therapy of Type II Diabetes: A Progressive Disease , 1995, Diabetes.

[42]  T. Schwartz,et al.  Ago-Allosteric Modulation and Other Types of Allostery in Dimeric 7TM Receptors , 2006, Journal of receptor and signal transduction research.

[43]  A. Goldstein,et al.  Activation of erythropoietin receptor in the absence of hormone by a peptide that binds to a domain different from the hormone binding site. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Dennis D. Kim,et al.  Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. , 2005, Diabetes care.

[45]  L. B. Knudsen,et al.  Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. , 2000, Journal of medicinal chemistry.

[46]  M. K. James,et al.  Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger". , 1996, Journal of medicinal chemistry.