Development of peptide 3D structure mimetics: Rational design of novel peptoid cholecystokinin receptor antagonists

The two hormones cholecystokinin and gastrin share the same C-terminal sequ ence of amino acids, namely Gly(29)-Trp(30)-Met(31)-Asp(32)-Phe(33)-NH2. Ne vertheless, this congruence has not precluded using this structure to devel op selective ligands for either CCK1 or CCK2 receptors. Manipulation of the hydrophobic residues at positions 31 and 33 gave a series of CCK1 tripepti de antagonists, typified by N-t-BOC-Trp-2-Nal-Asp-2-(phenyl)ethylamide (pK( B) 6.8 +/- 0.3). Molecular modeling was used to identify the bioactive conf ormation of these CCK1-selective compounds and prompted the design of new p eptoid structures. We aimed to maintain the conformation of the parent seri es by exploiting patterns of hydrogen-bonding and pi-stacking interactions present in the original molecule, rather than introducing additional covale nt bonds. The prototype, N-(succinyl-o-Asp-2-phenylethylamido)-L-Trp-2-( 2- naphthyl) ethylamide, was a potent and selective CCK1 antagonist (pK(B) 7.2 +/- 0.3). Furthermore, the new series showed patterns of biological activi ty that mirrored those of the parent tripeptides. These compounds contain e lements of both peptide primary and secondary structure and represent a nov el approach to designing peptidomimetics. Interesting results were obtained from comparing models of a representative tripeptide CCK1 antagonist with a conformation of CCK30-33 that others have proposed to be responsible for its activity at the CCK2 receptor. The results suggest that CCK1 and CCK2 r eceptors recognize enatiomeric dispositions of the Trp(30) indole, Asp(32) carboxylic acid, and C-terminal phenyl groups arrayed about a common backbo ne configuration. This "functional chirality" may underpin the mechanism by which these closely related receptor systems bind CCK30-33 and explain pat terns of selectivity observed with optical isomers of a number of peptoid a nd nonpeptide ligands.