Conformationally readdressed CCK‐B/δ‐opioid pepitide ligands

The sequence of a cholecystokinin (CCK) related peptide was modified to obtain analogues, which intereact selectively either with CCK‐B, or with δ‐opioid receptors. Two kinds of peptides were designed, namely, the cyclic peptides of the H‐Tyr‐cyclo(D‐Pen‐Gly‐Trp‐L‐/D‐3‐transmecaptoproline)‐Asp‐Phe‐NH₂ sequence (compounds 1a and 1b, respectively), and the linear peptides of the H‐Tyr‐D‐Val‐Gly‐Trp‐L/D‐3‐trans‐methylmercaptoproline‐Asp‐Phe‐NH₂ sequence (compounds 2a and 2b, respectively). The only difference between the chemical structures of the linear analogues compared to the cyclic ones is that one covalent bond has been eliminated and a sulfur atom is replaced by a methyl group. Molecular modeling showed that, among low‐energy conformers of cyclic compounds 1, there are three‐dimensional structures compatible to the model for δ‐ receptor‐ bound conformer, 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 compounds 1 and 2. The cyclic analogue 1a has K_i values of 4.5 and > 5000 n M at δ‐ and μ‐opioid receptors, respectively; IC₅₀ values of 3000 n M for both CCK‐A and CCK‐B receptors, whereas its linear counterpart 2a has k_i values of 462 and 229 nM at δ‐ and μ‐opioid receptors, 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 type of receptors (CCK‐B receptors) toward interaction with another type (δ‐opioid receptors) belonging to a different physiological system. This redirection could be performed by changing the conformational properties of the peptide with very minimal changes in its chemical structure. © 1995 John Wiley & Sons, Inc.