title: Biological and functional characteristics of a novel low-molecular weight antagonist of glucose-dependent insulinotropic polypeptide receptor, SKL-14959, in vitro and in vivo.
abstract: OBJECTIVE
  We recently discovered a glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist, SKL-14959. GIP plays a role in the glucose and lipid metabolism, and is associated with obesity and insulin resistance. Therefore, we aimed to ascertain the inhibitory potency and glucose and lipid metabolism of SKL-14959.
  
  
  METHODS
  SKL-14959 was evaluated for its binding affinity to each GIP, glucagon-like peptide-1 (GLP-1) and glucagon receptors by each labelled and non-labelled ligand; GIP-stimulated cyclic AMP (cAMP) production in CHO cells expressing human GIP receptor in vitro. Oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT) were performed to examine the insulinotropic effect on endogenous and exogenous GIP. Oil tolerance tests were also conducted to examine the lipid metabolism and the postheparin plasma lipase activity, lipoprotein lipase (LPL) and hepatic lipase (HL).
  
  
  RESULTS
  SKL-14959 selectively bound to GIP receptor and inhibited GIP-stimulated cAMP production with the Ki value of 55 nM and an IC(50) value of 2.9 µM, respectively. SKL-14959·Na significantly increased blood glucose levels, inhibited insulin secretion in OGTT and inhibited the plasma glucose lowering of exogenous GIP in IPGTT. Furthermore, SKL-14959 increased plasma triacylglycerol (TG) levels as well as suppressed the postheparin plasma lipase activity in an oil load test.
  
  
  CONCLUSIONS
  These data indicate that SKL-14959 is distinguished in the physiological phenotype of GIP following direct binding to the receptor.
authors.affiliation: Biological Research Group, Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho, Inabe-city, Mie, Japan. ta_nakamura@mb4.skk-net.com
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: H
authors.initials: H
authors.lastname: Tanimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Y
authors.initials: Y
authors.lastname: Tsubamoto
authors.forename: H
authors.initials: H
authors.lastname: Noda
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000187:drug effects / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008049:Lipase / Q000187:drug effects / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018027:Receptors, Glucagon / Q000187:drug effects / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D014280:Triglycerides; D052216:Glucagon-Like Peptide 1; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP; D008049:Lipase