title: Design and synthesis of N-terminal cyclic motilin partial peptides: a novel pure motilin antagonist.
abstract: Motilin antagonist was designed and synthesized on the basis of the structure-activity relationship analysis of porcine motilin that we reported recently. The drug design was performed on a specific concept to reduce a flexibility of peptide conformation of porcine motilin partial peptide by its cyclization. The cyclic peptide was synthesized using Boc (tert-butyloxycarbonyl) solid phase methodology, followed by cyclization using the azide procedure, and tested for the binding activity to motilin receptor and smooth muscle contractile activity. The cyclic peptides 3, 4, and 5 showed antagonistic property on contraction assay (pA2 [the negative logarithm of molar concentration of antagonist causing a 2-hold shift to the right of the concentration-response curve for motilin]: 4.5, 4.34, and 4.04, respectively, in rabbit duodenum) and no contractile activity even at high concentration.
authors.affiliation: Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Shizuoka, Japan. mharamura@chugaibio.com
authors.forename: M
authors.initials: M
authors.lastname: Haramura
authors.forename: A
authors.initials: A
authors.lastname: Okamachi
authors.forename: K
authors.initials: K
authors.lastname: Tsuzuki
authors.forename: K
authors.initials: K
authors.lastname: Yogo
authors.forename: M
authors.initials: M
authors.lastname: Ikuta
authors.forename: T
authors.initials: T
authors.lastname: Kozono
authors.forename: H
authors.initials: H
authors.lastname: Takanashi
authors.forename: E
authors.initials: E
authors.lastname: Murayama
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D008297:Male; D009037:Motilin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D011817:Rabbits; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; D009037:Motilin