Molecular design of potent specific antagonists for the gastrin and cholecystokinin receptors.

Widespread distribution of receptors for the peptide hormones cholecystokinin (CCK) and gastrin in the gut and in the CNS suggests therapeutic potential for selective antagonists of these hormones. Discovery of the natural product Asperlicin provided a new class of non-peptidal CCK antagonists, but oral bioavailability in this class remained elusive. With Asperlicin as a guide, the new, selective, orally bioavailable, high affinity CCK-A antagonist, MK-329 (L-364,718; Devazepide) and CCK-B/gastrin antagonist, L-365,260 have been developed. Biological profiles of these compounds are presented and results of early clinical evaluation of MK-329 are described. The significance of these agents as models for development of non-peptidal ligands for other receptors are briefly summarized.