title: Design and synthesis of motilin antagonists derived from the [1-4] fragment of porcine motilin.
abstract: A series of cyclic peptides having the general structure H-Phe-c[-N(epsilon)-Lys-X-NH-(CH(2))(n)-CO-] were designed on the basis of structure-activity relationship studies of motilin. All were motilin antagonists. The cyclic peptides, in which X is a 3-tert-butyl-substituted tyrosine residue (H-Phe-c[-N(epsilon)-Lys-Tyr(3-tBu)-beta Ala-] (3), H-Phe-c[-N(epsilon)-Lys-Tyr(3-tBu)-Gly-] (6), H-Phe-c[-N(epsilon)-Lys-Tyr(3-tBu)-Abu-] (7), and H-Phe-c[-N(epsilon)-Lys-Tyr(3-tBu)-Ahx-] (8)) showed potent motilin receptor antagonistic activity in the rabbit smooth muscle (pA(2) > 7). The 3-tert-butyl Tyr was found to be the moiety responsible for enhanced binding to the motilin receptor, while the size of the ring had little importance.
authors.affiliation: Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba-shi, Shizuoka 412-8513, Japan. mharamura@chugaibio.com
authors.forename: Masayuki
authors.initials: M
authors.lastname: Haramura
authors.forename: Akira
authors.initials: A
authors.lastname: Okamachi
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tsuzuki
authors.forename: Kenji
authors.initials: K
authors.lastname: Yogo
authors.forename: Makoto
authors.initials: M
authors.lastname: Ikuta
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kozono
authors.forename: Hisanori
authors.initials: H
authors.lastname: Takanashi
authors.forename: Eigoro
authors.initials: E
authors.lastname: Murayama
mesh_terms: D000818:Animals; D066298:In Vitro Techniques; D009037:Motilin / Q000737:chemistry*; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; D009037:Motilin