Motilin synthetic analogues 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 motilin receptor combined to a weak contractile activity. The following data suggest that motilin 1-12 [CH2 NH]10-11 is a potent motilin receptor antagonist. It showed a high affinity for the motilin receptor present on membranes of rabbit antrum (pIC50: 8.24 +/- 0.08 for the analogue 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 (pIC50: 8.91 +/- 0.06 in presence of saline versus 7.19 +/- 0.40 with the analogue). However, when injected i.v. in dogs, motilin 1-12 [CH2 NH]10-11 was undetectable in the peripheral blood, suggesting enzymatic degradation precluding its use in vivo.
Poitras
P
P
André-Viallet Clinical Research Center, Hôpital Saint-Luc, Université de Montréal, Québec, Canada.
Miller
P
P
Gagnon
D
D
St-Pierre
S
S
D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004386:Duodenum / Q000187:drug effects; D009037:Motilin / Q000031:analogs & derivatives* / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D011817:Rabbits; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*
D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; D009037:Motilin