CCK-A-SELECTIVE TETRAPEPTIDES CONTAINING LYS(N-E)-AMIDE RESIDUES - FAVORABLE IN-VIVO AND IN-VITRO EFFECTS OF N-METHYLATION AT THE ASPARTYL RESIDUE

Previous structure-activity studies on a series of CCK-A selective tet rapeptide agonists, typified by A-71623 (Boc-Trp-Lys(CONH-Ph-o-Me)-Asp -(N-Me)Phe-NH2), have shown that replacement of the Lys(N-epsilon-carb amoyl) substituent with N-epsilon-acyl substituents resulted in partia l agonists with moderate to high affinities for the CCK-A receptor and that replacement of the C-terminal dipeptide with either (N-Me)Asp-Ph e or (N-Me)Asp-(N-Me)Phe was highly favorable to in vitro and in vivo CCK activity. The present study demonstrates that although analogues i n the epsilon-amide series that are N-methylated at the Phe position a re weakly active or inactive in an in vivo rat appetite suppression as say, incorporation of (N-Me)Asp or (N-Me)Asp-(N-Me)Phe modifications i n this series results in analogues with markedly improved in vivo acti vity. In in vitro assays, there is minimal effect of N-methylation pat tern on binding affinity, whereas there is a trend toward improved fun ctional activity in the phosphatidylinositol hydrolysis assay in analo gues containing (N-Me)Asp.