Tetrapeptide CCK-A Agonists: Effect of Backbone N-Methylations on in vitro and in vivo CCK Activity

• Published in: Journal of medicinal chemistry 1994-03, Vol.37 (5), p.630-635
• Main Authors: Holladay, Mark W, Kopecka, Hana, Miller, Thomas R, Bednarz, Lisa, Nikkel, A. L, Bianchi, Bruce R, Witte, David G, Shiosaki, Kazumi, Lin, Chun Wel
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Chemistry; Cholecystokinin - analogs & derivatives; Cholecystokinin - chemistry; Eating - drug effects; Exact sciences and technology; Methylation; Molecular Sequence Data; Oligopeptides - chemical synthesis; Oligopeptides - metabolism; Oligopeptides - pharmacology; Organic chemistry; Peptides; Preparations and properties; Rats; Receptors, Cholecystokinin - metabolism; Structure-Activity Relationship; Sulfates - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00031a013

N-Methylation of backbone amide bonds was conducted on a tetrapeptide that had been identified previously (Shiosaki, K.; et al. J. Med. Chem. 1991, 34, 2387-2842) as a potent and selective CCK-A agonist. N alpha-Methylation at the position corresponding to Asp32 (CCK-33 numbering) was consistent with high affinity, efficacy, and selectivity for the CCK-A receptor. Combination of this (N-Me)Asp with the (N-Me)Phe modification also provided a highly active analogue. The observation of parallel structure-binding affinity profiles with respect to sites of N-methylation in the C-terminal regions of tetrapeptide vs heptapeptide CCK analogues suggests that the two series interact similarly with the CCK-A receptor.