Abstract

The selective recognition of the aminoterminal binding pharmacophore Tyr-D-Xaa-Phe of the opioid heptapeptide dermorphin, Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH₂ (DRM)¹, and of dermenkephalin, Tyr-D-Met-Phe-His-Leu-Met-Asp-NH₂ (DREK), by theμ.-opioid receptor and δ-opioid receptor, respectively, depends upon the constitution/conformation of the C-terminal tripeptide. The hybrid peptide DREK-[l-4]-DRM-[5-7] is very potent at, and exquisitely selective for theμ-opioid receptor, and differs only from dermenkephalin by its C-terminal tripeptide. Comparison of the structural features of DREK-[l-4]-DRM-[5-7] and dermenkephalin by nmr analysis and molecular modeling revealed striking differences, as well in the trans (Tyr⁵-Pro⁶) isomer (population 75%) than in the cis isomer. Whereas the folded C-terminal tail of dermenkephalin influenced the tertiary structure of the N-terminal tetrapeptide and placed the Tyr¹ and Phe³ aromatic rings in definite orientations that are best suited for the δ-receptor, there were only weak contacts, as shown by NOE data, between the aminoterminal and carboxyterminal parts of the hybrid peptide. This promoted increased flexibility of the whole backbone and relaxed orientations for the side-chains of Tyr¹ and Phe³ that are compatible with theμ-receptor but unsuitable for the δ-receptor. The steric hindrance introduced by Pro⁶ in DREK-[l-4]-DRM-[5-7], plus the absence of large hydrophobic side-chains in positions 5 and 6 may prevent close contacts between the N-terminal and C-terminal domains and reorientation of the main pharmacophoric elements Tyr¹ and Phe³.