MECHANISM OF DELTA-OPIOID RECEPTOR SELECTION BY THE ADDRESS DOMAIN OFDERMENKEPHALIN

Dermenkephalin (Tyr-D-Met-Phe-His-Leu-Met-AspNH(2)) is a highly potent and selective delta-opioid peptide isolated from frog skin. It was re cently recognized that the C-terminus His(4)-Leu(5)-Met(6)-Asp(7)NH(2) of dermenkephalin was responsible for the addressing of the peptide t owards the delta-opioid receptor. In order to investigate the role pla yed by residues 4, 5 and 6 in this 'delta address', we synthesized and evaluated 20 new analogues for their ability to displace tritiated li gands from mu- and delta-opioid sites. Results showed that position 4 of dermenkephalin contributes to 6 selectivity independently of delta- opioid receptor binding by preventing a high affinity mu binding. Posi tion 5 requires a hydrophobic side chain to enhance delta affinity. A high delta affinity was obtained with any amino acids introduced in po sition 6 suggesting that residue 6 serves as a neutral spacer. Thus, t he main features responsible for the high delta-opioid selectivity of dermenkephalin are electrostatic repulsions with the mu-opioid recepto r, additional hydrophobic interactions with the delta-opioid receptor and folding of the C-terminal domain.