title: An orally active motilin receptor antagonist, MA-2029, inhibits motilin-induced gastrointestinal motility, increase in fundic tone, and diarrhea in conscious dogs without affecting gastric emptying.
abstract: 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.
authors.affiliation: Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8513, Japan. ozakikni@chugai-pharm.co.jp
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Ozaki
authors.forename: Mitsu
authors.initials: M
authors.lastname: Onoma
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Muramatsu
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sudo
authors.forename: Shoshin
authors.initials: S
authors.lastname: Yoshida
authors.forename: Rie
authors.initials: R
authors.lastname: Shiokawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Yogo
authors.forename: Kenshi
authors.initials: K
authors.lastname: Kamei
authors.forename: Osamu
authors.initials: O
authors.lastname: Cynshi
authors.forename: Osamu
authors.initials: O
authors.lastname: Kuromaru
authors.forename: Theo L
authors.initials: TL
authors.lastname: Peeters
authors.forename: Hisanori
authors.initials: H
authors.lastname: Takanashi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005748:Gastric Fundus / Q000187:drug effects* / Q000502:physiology; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009037:Motilin; D009119:Muscle Contraction / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*
chemical_list: D005765:Gastrointestinal Agents; C528741:MA-2029; D009842:Oligopeptides; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; D009037:Motilin