title: CCK-A-selective tetrapeptides containing lys(N epsilon)-amide residues: favorable in vivo and in vitro effects of N-methylation at the aspartyl residue.
abstract: 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.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bennett
authors.forename: A L
authors.initials: AL
authors.lastname: Nikkel
authors.forename: B R
authors.initials: BR
authors.lastname: Bianchi
authors.forename: T R
authors.initials: TR
authors.lastname: Miller
authors.forename: L
authors.initials: L
authors.lastname: Bednarz
authors.forename: D G
authors.initials: DG
authors.lastname: Witte
authors.forename: M
authors.initials: M
authors.lastname: Stashko
authors.forename: S S
authors.initials: SS
authors.lastname: Wang
authors.forename: P A
authors.initials: PA
authors.lastname: Gore
authors.forename: K E
authors.initials: KE
authors.lastname: Asin
mesh_terms: 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
chemical_list: D001067:Appetite Depressants; D009842:Oligopeptides; D010716:Phosphatidylinositols; D011949:Receptors, Cholecystokinin; D013758:Tetragastrin; C066278:A 71623; D001224:Aspartic Acid; D002766:Cholecystokinin; D008239:Lysine