Design and synthesis of novel tetra-peptide motilin agonists.

Abstract 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 μM, respectively. Interaction of the tryptophan aliphatic side chain with motilin receptor appears to influence the signal transduction via motilin receptor.