DERMENKEPHALIN AND DELTORPHIN-I REVEAL SIMILARITIES WITHIN LIGAND-BINDING DOMAINS OF MU-OPIOID AND DELTA-OPIOID RECEPTORS AND AN ADDITIONAL ADDRESS SUBSITE ON THE DELTA-RECEPTOR

Dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), dermenkephalin (Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2) and deltorphin I (Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) are the first naturally occurring peptides highly potent for and almost specific to the μ- and δ -opioid receptors, respectively. The amino-terminal domains Tyr-D-X-Phe (where X is either Ala or Met) of these peptides behave as selective and potent μ-receptor ligands. Routing of Tyr-D-X-Phe to the δ - or the μ- receptor is associated with the presence or the absence at the C-terminus of an additional hydrophobic and negatively charged tetrapeptide by-passing the μ-addressing ability of the amino-terminal moiety. A study of 20 Tyr-D-X-Phe-Y-NH2 analogs with substitution of X and Y by neutral, hydrophobic, aromatic amino acids as well as by charged amino acid residues shows that tetrapeptides maintain high binding affinity and selectivity for the μ-opioid receptor. Although residue in position 4 serves a δ-address function, the tripeptide motif at the C-terminus of dermenkephalin and deltorphin I are critical components for high selectivity at δ -opioid receptor. Results demonstrate that μ- and δ -opioid receptors share topologically equivalent ligand-binding domains, or ligand-binding sequences similarities, that recognized Tyr-D-X-Phe as a consensus message-binding sequence. The δ -receptor additionally contains a unique address subsite at or near the conserved binding domain that accomodates the C-terminal tetrapeptide motif of dermenkephalin and deltorphin I. © 1991.