title: GSK962040: a small molecule motilin receptor agonist which increases gastrointestinal motility in conscious dogs.
abstract: BACKGROUND
  GSK962040, a small molecule motilin receptor agonist, was identified to address the need for a safe, efficacious gastric prokinetic agent. However, as laboratory rodents lack a functional motilin system, studies in vivo have been limited to a single dose, which increased defecation in rabbits. Motilin agonists do not usually increase human colonic motility, so gastric prokinetic activity needs to be demonstrated.
  
  
  METHODS
  The effect of intravenous GSK962040 on gastro-duodenal motility was assessed in fasted dogs implanted with strain gauges. Activity was correlated with blood plasma concentrations of GSK962040 (measured by HPLC-MS/MS) and potency of GSK962040 at the dog recombinant receptor [using a Fluorometric Imaging Plate Reader (Molecular Devices, Wokingham, UK) after expression in HEK293 cells].
  
  
  RESULTS
  GSK962040 activated the dog motilin receptor (pEC(50) 5.79; intrinsic activity 0.72, compared with [Nle(13) ]-motilin). In vivo, GSK962040 induced phasic contractions, the duration of which was dose-related (48 and 173 min for 3 and 6 mg kg(-1) ), driven by mean plasma concentrations >1.14 μmol L(-1) . After the effects of GSK962040 faded, migrating motor complex (MMC) activity returned. Migrating motor complex restoration was unaffected by 3 mg kg(-1) GSK962040 but at 6 mg kg(-1) , MMCs returned 253 min after dosing, compared with 101 min after saline (n=5 each).
  
  
  CONCLUSIONS
  The results are consistent with lower potency for agonists at the dog motilin receptor, compared with humans. They also define the doses of GSK962040 which stimulate gastric motility. Correlation of in vivo and in vitro data in the same species, together with plasma concentrations, guides further studies and translation to other species.
authors: Zablocki VAMC, Wisconsin Corporation for Biomedical Research, Milwaukee, WI, USA.
authors: S
authors: S
authors: Leming
authors: J
authors: J
authors: Broad
authors: S J
authors: SJ
authors: Cozens
authors: M
authors: M
authors: Otterson
authors: W
authors: W
authors: Winchester
authors: K
authors: K
authors: Lee
authors: G E
authors: GE
authors: Dukes
authors: G J
authors: GJ
authors: Sanger
mesh_terms: D000818:Animals; D003243:Consciousness; D004285:Dogs; D005769:Gastrointestinal Motility / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists*; D018013:Receptors, Neuropeptide / Q000819:agonists*; D014162:Transfection
chemical_list: C541863:N-(3-fluorophenyl)-1-((4-(((3S)-3-methyl-1-piperazinyl)methyl)phenyl)acetyl)-4-piperidinamine; D010879:Piperazines; D010880:Piperidines; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor