MOTILIN SYNTHETIC ANALOGS AND MOTILIN RECEPTOR ANTAGONISTS

While studying the structure-activity characteristics of motilin with motilin synthetic analogues, two compounds, motilin 1-12 [CH2 NH](3-4) and motilin 1-12 [CH2 NH](10-11), showed high affinity for the motili n receptor combined to a weak contractile activity. The following data suggest that motilin 1-12 [CH2 NH](10-11) is a potent motilin recepto r antagonist. It showed a high affinity for the motilin receptor prese nt on membranes of rabbit antrum (pIC(50): 8.24 +/- 0.08 for the analo gue vs 8.96 +/- 0.02 for the native peptide). When tested in vitro on strips of rabbit duodenum, the dose-response curve to motilin 1-22 was displaced to the right with motilin 1-12 [CH2 NH](10-11) (pIC(50): 8. 91 +/- 0.06 in presence of saline versus 7.19 +/- 0.40 with the analog ue). However, when injected i.v. in dogs, motilin 1-12 [CH2 NH](10-11) was undetectable in the peripheral blood, suggesting enzymatic degrad ation precluding its use in vivo. (C) 1994 Academic Inc. Press, Inc.