The pharmacological properties of
MA-2029, a selective and competitive
motilin receptor antagonist, were investigated in conscious dogs after
oral administration. Gastrointestinal contractile activity was recorded by chronically implanted force transducers. The proximal gastric volume was measured with a barostat under constant pressure. Gastric emptying was examined using the
paracetamol absorption test.
MA-2029 (0.3-10 mg/kg, p.o.) administered in the interdigestive state inhibited gastrointestinal contractions induced by
motilin (3 microg/kg, i.v.) in a dose-dependent manner.
MA-2029 (0.3-3 mg/kg, p.o.) also inhibited the occurrence of spontaneous phase III contractions, even though
MA-2029 had no effect on basal gastrointestinal motility or basal gastric emptying even
at 10 and 30 mg/kg p.o. The inhibitory effect of
MA-2029 on
motilin-induced gastrointestinal motility corresponded to its plasma concentration.
Motilin (0.3 microg/kg/h, i.v. infusion) reduced the proximal gastric volume by about 50% of control during isobaric distension. This effect was also inhibited by
MA-2029 (1-10 mg/kg, p.o.) in a dose-dependent manner. In the digestive state, injection of
motilin (3 microg/kg, i.v.) induced
diarrhea in 9 of 11 dogs.
MA-2029 (1-30 mg/kg, p.o.) reduced the incidence of
diarrhea induced by
motilin in a dose-dependent manner. The results indicate that
MA-2029 inhibits hypermotility induced by
motilin in conscious dogs without having an effect on the basal gastrointestinal tone or gastric emptying rate.
MA-2029 may be useful in treating
gastrointestinal disorders in which the pathogenesis involves the elevation of circulating
motilin.