Design and synthesis of novel tetra-peptide motilin agonists.
A series of novel tetra-peptide motilin agonists, having the general structure H-Phe-Val-X-Ile-NH(2), were designed, on the basis of structure-activity relationship studies of motilin. Peptides, in which X is a side chain substituted tryptophan residue, have agonistic activity. H-Phe-Val-Trp(2'-CH(2)CH(2)OH)-Ile-NH(2)(7), H-Phe-Val-Trp(2'-SCH(3))-Ile-NH(2)(8), and H-Phe-Val-Trp(2'-SCH(2)CH(2)CH(3))-Ile-NH(2)(9), showed an EC(50) for contractile activity in the rabbit smooth muscle of 14.1+/-3.2, 12.9+/-4.1, and 4.6+/-1.6 microM, respectively. Interaction of the tryptophan aliphatic side chain with motilin receptor appears to influence the signal transduction via motilin receptor.
Haramura
Masayuki
M
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, 412-8513, Shizuoka, Japan. mharamura@chugaibio.com
Tsuzuki
Kouichi
K
Okamachi
Akira
A
Yogo
Kenji
K
Ikuta
Makoto
M
Kozono
Toshiro
T
Takanashi
Hisanori
H
Murayama
Eigoro
E
D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D005765:Gastrointestinal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects; D007422:Intestines / Q000187:drug effects / Q000502:physiology; D008297:Male; D009037:Motilin / Q000819:agonists* / Q000378:metabolism / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D005765:Gastrointestinal Agents; D009842:Oligopeptides; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; D009037:Motilin