Neuroendocrine systems function to coordinate complex physiological and homeostatic processes, and the peptide hormone ghrelin is a key factor in the neuroendocrine control of nutrient metabolism. Ghrelin is secreted primarily by the stomach and reaches peak plasma levels in anticipation of a meal. It then acts at its specific G-protein-coupled receptor (GhrR/GHSR-1a) to potently stimulate food intake (FI) and nutrient storage. Consistent with its role in determining the fate of consumed nutrients, ghrelin has a potent prokinetic action on the gastrointestinal (GI) tract. In this study, BMS-604992 is a selective, orally active small-molecule growth hormone secretagogue receptor (GHSR) agonist. BMS-604992 demonstrates high-affinity binding (Ki=2.3 nM) and potent functional activity (EC50=0.4 nM). It can stimulate food intake in rodents.
BMS-604992 exhibits high-affinity binding and potent functional activity for ghrelin receptor. It results in a significant increase in gastric emptying compared with vehicle-treated mice.BMS-604992 Shows a dose-linear increase in plasma concentrations at the 1 hour time point and elicits a dose-responsive increase in food intake relative to vehicle-treated controls, with a minimum effective dose of approximately 10 mg/kg. In addition, BMS-604992 produces a significant difference at the 5 minutes time point. It also increases food intake approximately 2-fold compared with vehicle-treated controls.
In summary, oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. BMS-604992 is a selective, orally active GHSR agonist. It stimulates gastric emptying, smallintestinal transit, and fecal output in addition to stimulating food intake. In addition, BMS-604992 ameliorates opiate-induced bowel dysfunction. Thus, it has the potential for a range of gastrointestinal dysmotility disorders research.
Charoenthongtrakul S, et, al. J Pharmacol Exp Ther. 2009 Jun;329(3):1178-86.