CONFORMATIONALLY READDRESSED CCK-B DELTA-OPIOID PEPTIDE LIGANDS/

The sequence of a cholecystokinin (CCK) related peptide was modified t o obtain analogues, which interact selectively either with CCK-B, or w ith delta-opioid receptors. Two kinds of peptides were designed, namel y, the cyclic peptides of the en-Gly-Trp-L/D3-trans-mercaptoproline)-A sp-Phe-NH2 sequence (compounds 1a and 1b, respectivelyl, and the linea r peptides of the ly-Trp-L/D-trans-methylmercaptoproline-Asp-Phe-NH2 s equence (compounds 2a and 2b, respectively). The only differ ence betw een the chemical structures of the linear analogues compared to the cy clic ones is that one covalent bond has been eliminated and a sulfur a tom is replaced by a methyl group. Molecular modeling showed that, amo ng low-energy conformers of cyclic compounds 1, there are three-dimens ional structures compatible to the model for delta-receptor-bound conf ormer suggested earlier [G. V. Nikiforovich, V. J. Hruby, O. Prakash, and C. A. Gehrig (1991) Biopolymers, vol. 31, pp. 941-955]. Results of binding assays fully supported the rationale for the design of compou nds I and 2, The cyclic analogue la has K-i values of 4.5 and > 5000 n M at delta- and mu-opioid receptors, respectively, IC50 values of 300 0 n M for both CCK-A and CCK-B receptors, whereas its linear counterpa rt 2a has K-i values of 462 and 229 nM at delta- and mu-opioid recepto rs, respectively; and IC50 values of 1.6 and > 10,000 nM for CCK-A and CCK-B receptors, respectively. The results of this study demonstrate a possibility to redirect a peptide sequence that interacts with one t ype of receptors (CCK-B receptors) toward interaction with another typ e (delta-opioid receptors) belonging to a different physiological syst em. This r edirection could be performed by changing the conformationa l properties of the peptide with very minimal changes in its chemical structure. (C) 1995 John Wiley & Sons, Inc.