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Synthesis and biological evaluation of lorglumide‐like hybrid cholecystokinin‐A receptor antagonists
Author(s) -
van der Bent Arie,
van den Brink Ingrid,
Ijzerman Adriaan P.,
van Wijngaarden Ineke,
Soudijn Willem
Publication year - 1994
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430310307
Subject(s) - moiety , chemistry , stereochemistry , cholecystokinin receptor , antagonist , amino acid , receptor , biochemistry
Abstract The evaluation of gross structural homologies between the competitive cholecystokinin‐A (CCK‐A) receptor antagonists lorglumide and devazepide formerly enabled the development of compact hybrid analogues [Van der Bent et al. (1992): J Med Chem 35:1042–1049]. In the follow‐up study described here, we aimed to closely examine the structural and functional relationship between N‐acyglutamic acids like lorglumide and our hybrid derivatives. For this purpose, the most potent hybrid CCK‐A antagonist (K i = 0.09 μM) was modified by the addition of the propionic acid moiety that is unique to the N‐acylglutamic acids. Additionally, a number of propionic acid and butyric acid derivatives were prepared in order to explore the SAR profile of the carboxylic acid moiety in this series. The prepared compounds were tested in vitro as antagonists of the binding of [ 3 H]‐(±)‐L‐364,718 to rat pancreas membranes. With CCK‐A affinities above 1 μM, all derivatives of the initial hybrid structure, including the propionic acid derivative that closely resembles lorglumide, proved to be considerably less potent. It would appear that the retained structural differences between lorglumide and the novel hybrid antagonists result in a divergence of their binding modes that precludes a favourable interaction of the added functionality of the latter compounds. Alternatively, the obtained results may question the vital role that has been attributed to the carboxylic acid function of the N‐acylglutamic acids as a counterion to a cationic residue in the binding site. © 1994 Wiley‐Liss, Inc.