CCK-A-selective tetrapeptides containing lys(N epsilon)-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 tetrapeptide 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-carbamoyl) substituent with N epsilon-acyl substituents resulted in partial agonists with moderate to high affinities for the CCK-A receptor and that replacement of the C-terminal dipeptide with either (N-Me)Asp-Phe 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 in the epsilon-amide series that are N-methylated at the Phe position are weakly active or inactive in an in vivo rat appetite suppression assay, incorporation of (N-Me)Asp or (N-Me)Asp-(N-Me)Phe modifications in this series results in analogues with markedly improved in vivo activity. In in vitro assays, there is minimal effect of N-methylation pattern on binding affinity, whereas there is a trend toward improved functional activity in the phosphatidylinositol hydrolysis assay in analogues containing (N-Me)Asp.
Bennett
M J
MJ
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Nikkel
A L
AL
Bianchi
B R
BR
Miller
T R
TR
Bednarz
L
L
Witte
D G
DG
Stashko
M
M
Wang
S S
SS
Gore
P A
PA
Asin
K E
KE
D000595:Amino Acid Sequence; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology; D001224:Aspartic Acid / Q000737:chemistry*; D002540:Cerebral Cortex / Q000737:chemistry; D002766:Cholecystokinin / Q000031:analogs & derivatives* / Q000737:chemistry; D004435:Eating / Q000187:drug effects; D006168:Guinea Pigs; D006868:Hydrolysis; D008239:Lysine; D008745:Methylation; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010179:Pancreas / Q000737:chemistry / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013758:Tetragastrin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
D001067:Appetite Depressants; D009842:Oligopeptides; D010716:Phosphatidylinositols; D011949:Receptors, Cholecystokinin; D013758:Tetragastrin; C066278:A 71623; D001224:Aspartic Acid; D002766:Cholecystokinin; D008239:Lysine