title: Oral administration of MA-2029, a novel selective and competitive motilin receptor antagonist, inhibits motilin-induced intestinal contractions and visceral pain in rabbits.
abstract: The pharmacological properties of MA-2029, a novel motilin receptor antagonist, were investigated. In vitro, MA-2029 (1 to 30 nM) competitively inhibited motilin-induced contractions in isolated rabbit duodenal longitudinal muscle strips, with a pA2 value of 9.17+/-0.01 (n=5). However, contractile responses to acetylcholine and substance P were unaffected even at 1 microM of MA-2029. MA-2029 concentration-dependently inhibited the binding of [125 I]motilin to motilin receptors in a homogenate of rabbit colon smooth muscle tissue and membranes of HEK 293 cells expressing human motilin receptors. The pKi of MA-2029 was 8.58+/-0.04 in the rabbit colon homogenate (n=4) and 8.39 in the HEK 293 cells (mean of duplicate experiments). In vivo, orally-administered MA-2029 (3 to 30 mg/kg) dose-dependently inhibited colonic contractions induced by motilin (3 microg/kg, i.v.) in conscious rabbits. Inhibition was caused by all doses at 30 min after administration and by 10 mg/kg or more at 4 h after administration. The plasma concentration of MA-2029 correlated with its inhibitory effect. Furthermore, the oral administration of MA-2029 (0.3 to 3 mg/kg) also inhibited abdominal muscle contractions (an index of the visceral pain) induced by intravenous infusion of motilin (3 microg/kg/h) during colorectal distension in conscious rabbits. These results indicate that MA-2029 is an orally active, selective and competitive motilin receptor antagonist. It is suggested that this compound may be useful for gastrointestinal disorders associated with disturbed gastrointestinal motility such as irritable bowel syndrome.
authors.affiliation: Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., via Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sudo
authors.forename: Shoshin
authors.initials: S
authors.lastname: Yoshida
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Ozaki
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Muramatsu
authors.forename: Mitsu
authors.initials: M
authors.lastname: Onoma
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; D001667:Binding, Competitive; D002460:Cell Line; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D008297:Male; D009037:Motilin / Q000187:drug effects* / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects*; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D010147:Pain Measurement; D011817:Rabbits; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*
chemical_list: C528741:MA-2029; D009842:Oligopeptides; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; D009037:Motilin