Synthesis and biological activity of CCK heptapeptide analogues. Effects of conformational constraints and standard modifications on receptor subtype selectivity, functional activity in vitro, and appetite suppression in vivo

A series of modifications of the CCK sub(7) analogue (des-NH sub(2))Tyr(SO sub(3) super(-))-Nle-Gly-Trp-Nle-Asp-Phe-NH sub(2) was prepared and tested for binding to guinea pig CCK-A and CCK-B receptors and in CCK-A-mediated functional assays. Selected analogues also were tested for appetite suppress...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 1992-01, Vol.35 (13), p.2919-2927
Main Authors: Holladay, M W, Bennett, MJ, Tufano, MD, Lin, C W, Asin, KE, Witte, D G, Miller, T R, Bianchi, B R, Nikkel, AL
Format: Article
Language:English
Subjects:
analogs
biological activity
cholecystokinin
heptapeptides
peptide synthesis
synthesis
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:A series of modifications of the CCK sub(7) analogue (des-NH sub(2))Tyr(SO sub(3) super(-))-Nle-Gly-Trp-Nle-Asp-Phe-NH sub(2) was prepared and tested for binding to guinea pig CCK-A and CCK-B receptors and in CCK-A-mediated functional assays. Selected analogues also were tested for appetite suppressant activity in rats. Several conformationally restricted residues in the C-terminal tetrapeptide region, including Delta super(Z)-Phe super(33), (N-Me)Phe super(33), (N-Me)Asp super(32), (N-Me)Leu super(31), and 3PP super(31) (3PP = trans-3-n-propyl-L-proline) were found to be acceptable modifications at one or both receptor subtypes. The (N-Me)Asp super(32) and (N-Me)Leu super(31) modifications afforded potent and selective CCK-A and CCK-B ligands, respectively.
ISSN:0022-2623