Conformation-activity relationships of cyclo-constrained μ/δ opioid agonists derived from the N-terminal tetrapeptide segment of dermorphin/deltorphin

摘要

The N-terminal tetrapeptide segments of dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) and deltorphin (Tyr-D-Ala-Phe-Asp/Glu-Val-Val-Gly-NH2) are agonists at the opioid receptors μ and δ, respectively. (D-Arg,Lys)-dermorphin(1-4) amide (Tyr-D-Arg-Phe-Lys-NH2, DALDA) and [Dmt~1]DALDA (Dmt is 2',6'-dimethyl-tyrosine) are among the most potent and selective μ-agonists reported to date, both in vitro (the latter one having picomolar μ receptor affinity) and in vivo. In this communication, conformation-activity studies of cyclic tetrapeptide analogs of dermorphin/deltorphin are presented and discussed. They include the peptide Tyr-c[D-Cys-Phe-Cys]NH2, constrained via an S~γS'~γ disulfide between Cys and Cys, and its dicarba analogs, the C~γC'~γ-saturated and -olefinic ones. They are potent nonselective or moderately μ-selective opioid agonists in vitro [1] (Table 1). With a major structural constraint imposed by the 11-membered ring spanning residues 2-4, they are expected to manifest well-defined conformations of the backbone. Given the small size and confirmed bioactivity of the peptides [1], there is a good chance that their conformations determined in solution would correspond to the receptor-bound ones. We used 2D-NMR in H2O/D2O supported with molecular dynamics (MD) in this study.