Enhanced gastrointestinal motility with orally active ghrelin receptor agonists.
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.
Charoenthongtrakul
Soratree
S
Elixir Pharmaceuticals, Inc., 12 Emily Street, Cambridge, MA 02139, USA.
Giuliana
Derek
D
Longo
Kenneth A
KA
Govek
Elizabeth K
EK
Nolan
Anna
A
Gagne
Samantha
S
Morgan
Kristen
K
Hixon
Jeffrey
J
Flynn
Neil
N
Murphy
Brian J
BJ
Hernández
Andres S
AS
Li
Jun
J
Tino
Joseph A
JA
Gordon
David A
DA
DiStefano
Peter S
PS
Geddes
Brad J
BJ
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001913:Bowen's Disease / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D002490:Central Nervous System / Q000187:drug effects; D003672:Defecation / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005746:Gastric Emptying / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects*; D005772:Gastrointestinal Transit / Q000187:drug effects; D054439:Ghrelin / Q000008:administration & dosage* / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D036361:Peptide Hormones / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
D054439:Ghrelin; D036361:Peptide Hormones; D054440:Receptors, Ghrelin; D009020:Morphine