title: In vitro pharmacological characterization of mitemcinal (GM-611), the first acid-resistant non-peptide motilin receptor agonist, in smooth muscle of rabbit small intestine.
abstract: The pharmacological properties of mitemcinal (GM-611), the first acid-resistant non-peptide motilin agonist, were investigated in the smooth muscle of the rabbit small intestine and compared with porcine motilin (pMTL), erythromycin A (EMA) and its derivatives (EM-523, EM-574 and ABT-229). Mitemcinal, pMTL, EMA, EM-523, EM-574 and ABT-229 produced concentration-dependent contractions with approximately the same maximum contractions in the isolated rabbit duodenum longitudinal strips. The contractile response to mitemcinal or pMTL was competitively inhibited by a selective motilin antagonist, GM-109. The pA(2) values for GM-109 as an antagonist of mitemcinal and pMTL showed approximately the same values. However, the concentration-dependent contractile responses to mitemcinal or pMTL were not affected by pretreatment with atropine, tetrodotoxin, hexamethonium, naloxone or tropisetron. The removal of calcium ions from the medium and pretreatment with verapamil greatly suppressed the contractions induced by mitemcinal and pMTL. The contractile response to mitemcinal was not affected by preincubation in acidic solutions, while those of EM-523, EM-574 and ABT-229 were strongly diminished in the same condition. Mitemcinal as well as other motilin agonists displaced (125)I-pMTL bound to a homogenate of the rabbit duodenum muscle tissue. The displacement curves of all these compounds were parallel. These results indicate that mitemcinal is a selective and full motilin receptor agonist in the smooth muscle of the rabbit small intestine and that this agent has an excellent acid-resistant property.
authors.affiliation: Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, Shizuoka, Japan. takanashihsn@chugai-pharm.co.jp
authors.forename: Hisanori
authors.initials: H
authors.lastname: Takanashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Yogo
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Ozaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koga
authors.forename: Zen
authors.initials: Z
authors.lastname: Itoh
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002122:Calcium Chloride / Q000494:pharmacology; D004110:Diltiazem / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018738:Hexamethonium / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007421:Intestine, Small / Q000187:drug effects* / Q000502:physiology; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009270:Naloxone / Q000494:pharmacology; D011817:Rabbits; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists*; D018013:Receptors, Neuropeptide / Q000819:agonists*; D013779:Tetrodotoxin / Q000494:pharmacology; D000077526:Tropisetron; D014700:Verapamil / Q000494:pharmacology
chemical_list: D007211:Indoles; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; C090116:Idremcinal; D009270:Naloxone; D018738:Hexamethonium; D013779:Tetrodotoxin; C114264:Alemcinal; D004917:Erythromycin; D000077526:Tropisetron; C103741:mitemcinal; D001285:Atropine; C061752:EM 523; D014700:Verapamil; D004110:Diltiazem; D002122:Calcium Chloride; D000109:Acetylcholine