Conformational determinants of high affinity delta receptor binding of opioid peptides

Detailed conformational analysis of linear and cyclic delta-selective opioid peptides was performed in conjunction with computer-analyzed receptor binding studies with the aim of determining conformational requirements for high affinity binding of peptides to the delta-receptor. The four linear delta-selective hexapeptides included in this study were: DSLET (Tyr-D-Ser-Gly-Phe-Leu-Thr) and its D-Thr2 analog (DTLET) and two t-butyl ether analogs. In one analog an O-t-butyl group replaces the D-Ser2OH and in the other a second O-t-butyl group replaces the D-Thr6OH group as well. This study also includes seven cyclic pentapeptides of the type: Tyr-Cys(Pen-Gly-Phe-Cys(Pen) with various combinations of DL-cysteine and DL-penicillamine (beta-dimethyl cysteine) as the second and fifth residues resulting in varying delta affinities and selectivities. Four (DPLPE, DPDPE, DPLCE, and DCLPE) have both high delta affinity and selectivity; two (DCDCE and DCLCE) have high affinity at both delta- and mu-receptors, and one (LCLCE) has low affinity for both receptors. Our investigation has shown that all analogs that have high affinity at the delta receptor have a unique common low energy conformer. This compact conformer contains intramolecular H-bonds and is very different from the beta II-turn-type structure associated with high affinity mu-receptor binding deduced in our previous work.