SYNTHESIS AND BIOLOGICAL EVALUATION OF LORGLUMIDE-LIKE HYBRID CHOLECYSTOKININ-A RECEPTOR ANTAGONISTS

The evaluation of gross structural homologies between the competitive cholecystokinin-A (CCK-A) receptor antagonists lorglumide and devazepi de formerly enabled the development of compact hybrid analogues [Van d er Bent et al. (1992): J Med Chem 35:1042-1049]. In the follow-up stud y described here, we aimed to closely examine the structural and funct ional relationship between N-acylglutamic acids like lorglumide and ou r hybrid derivatives. For this purpose, the most potent hybrid CCK-A a ntagonist (K-i = 0.09 mu M) was modified by the addition of the propio nic acid moiety that is unique to the N-acylglutamic acids. Additional ly, a number of propionic acid and butyric acid derivatives were prepa red in order to explore the SAR profile of the carboxylic acid moiety in this series. The prepared compounds were tested in vitro as antagon ists of the binding of [H-3]-(+/-)-L-364,718 to rat pancreas membranes . With CCK-A affinities above 1 mu M, all derivatives of the initial h ybrid 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 functionali ty of the latter compounds. Alternatively, the obtained results may qu estion the vital role that has been attributed to the carboxylic acid function of the N-acylglutamic acids as a counterion to a cationic res idue in the binding site. (C) 1994 Wiley-Liss, Inc.