QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jpet.108.150193v1 329/3/1178    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Charoenthongtrakul, S. Articles by Geddes, B. J. PubMed PubMed Citation Articles by Charoenthongtrakul, S. Articles by Geddes, B. J.

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Enhanced Gastrointestinal Motility with Orally Active Ghrelin Receptor Agonists

Elixir Pharmaceuticals, Inc., Cambridge, Massachusetts (S.C., D.G., K.A.L., E.K.G., A.N., S.G., K.M., J.H., P.S.D., B.J.G.); and Bristol-Myers Squibb, Princeton, New Jersey (N.F., B.J.M., A.S.H., J.L., J.A.T., D.A.G.)

The orexigenic peptide ghrelin has been shown to have prokinetic activity in the gastrointestinal (GI) system of several species, including humans. In this series of experiments, we have evaluated the prokinetic activity of novel, small-molecule ghrelin receptor (GhrR) agonists after parenteral and peroral dosing in mice and rats. Gastric emptying, small intestinal transport, and fecal output were determined after intraperitoneal and intracerebroventricular dosing of GhrR agonists, using ghrelin as a positive control. These same parameters were evaluated after oral gavage dosing of the synthetic agonists. Regardless of dose route, GhrR agonist treatment increased gastric emptying, small intestinal transit, and fecal output. However, fecal output was only increased by GhrR agonist treatment if mice were able to feed during the stimulatory period. Thus, GhrR agonists can stimulate upper GI motility, and the orexigenic action of the compounds can indirectly contribute to prokinetic activity along the entire GI tract. The orexigenic and prokinetic effects of either ghrelin or small-molecule GhrR agonists were selective for the GhrR because they were absent when evaluated in GhrR knockout mice. We next evaluated the efficacy of the synthetic GhrR agonists dosed in a model of opiate-induced bowel dysfunction induced by a single injection of morphine. Oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. These data demonstrate the potential utility of GhrR agonists for treating gastrointestinal hypomotility disorders.

Address correspondence to: Dr. Brad J. Geddes, Elixir Pharmaceuticals, Inc., 12 Emily Street, Cambridge, MA 02139. E-mail: bgeddes{at}elixirpharm.com