2-Oxopyrrolidines and 6-Oxoperhydropyrrolo[1, 2-a]pyrazines as Templates in the Search for Nonpeptide Cholecystokinin Ligands

Abstract

In order to find new classes of non-peptide cholecystokinin (CCK) ligands, the conformational restriction of a series of weak 3-oxoindolizidine-based CCK antagonists has been both decreased and increased. This tactic yielded a series of monocyclic 2-oxopyrrolidine derivatives 4 with selectively for CCK-A or CCK-B receptors and with slightly improved binding affinity at the CCK-A receptor subtype with respect to the model 3-oxoindolizidines. In contrast, the incorporation o the Trp residue at the secondary amino group of a pyrrolo[1, 2-a]pyrazine template 5, involving a drastic restriction in the conformational flexibility of the molecule, resulted in a series of bicyclic derivatives that did not bind to CCK receptors at concentrations up to 10^-5 M.