The delta-selective opioid peptide dermenkephalin and the mu-selective hybrid peptide dermenkephalin-[1-4]-dermorphin-[5-7] display strikingly different conformations despite identical tetrapeptide N-termini. A quantitative 2-D NMR and molecular modeling analysis.

The selective recognition of the aminoterminal binding pharmacophore Tyr-D- Xaa-Phe of the opioid heptapeptide dermorphin, Tyr-D-Ala-Phe-Gly-Tyr-Pro-Se r-NH2 (DRM)(1), and of dermenkephalin, Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 (D REK), by the mu-opioid receptor and delta-opioid receptor, respectively, de pends upon the constitution / conformation of the C-terminal tripeptide. Th e hybrid peptide DREK-[1-4]-DRM-[5-7] is very potent at, and exquisitely se lective for the mu-opioid receptor, and differs only from dermenkephalin by its C-terminal tripeptide. Comparison of the structural features of DREK-[ 1-4]-DRM-[5-7] and dermenkephalin by nmr analysis and molecular modeling re vealed striking differences, as well in the trans (Tyr(5) - Pro(6)) isomer (population 75%) than in the cis isomer.. Whereas the folded C-terminal tai l of dermenkephalin influenced the tertiary structure of the N-terminal tet rapeptide and placed the Tyr(1) and Phe(3) aromatic rings in definite orien tations that are best suited for the delta-receptor, there were only weak c ontacts, as shown by NOE data, between the aminoterminal and carboxytermina l parts of the hybrid peptide. This promoted increased flexibility of the w hole backbone and relaxed orientations for the side-chains of Tyr(1) and Ph e(3) that are compatible with the mu-receptor but unsuitable for the delta- receptor. The steric hindrance introduced by Pro(6) in DREK-[1-4]-DRM-[5-7] , plus the absence of large hydrophobic side-chains in positions 5 and 6 ma y prevent close contacts between the N-terminal and C-terminal domains and reorientation of the main pharmacophoric elements Tyr(1) and Phe(3).