Mechanism of delta-opioid receptor selection by the address domain of dermenkephalin.
Dermenkephalin (Tyr-D-Met-Phe-His-Leu-Met-AspNH2) is a highly potent and selective delta-opioid peptide isolated from frog skin. It was recently recognized that the C-terminus His4-Leu5-Met6-Asp7NH2 of dermenkephalin was responsible for the addressing of the peptide towards the delta-opioid receptor. In order to investigate the role played by residues 4, 5 and 6 in this 'delta address', we synthesized and evaluated 20 new analogues for their ability to displace tritiated ligands from mu- and delta-opioid sites. Results showed that position 4 of dermenkephalin contributes to delta selectivity independently of delta-opioid receptor binding by preventing a high affinity mu binding. Position 5 requires a hydrophobic side chain to enhance delta affinity. A high delta affinity was obtained with any amino acids introduced in position 6 suggesting that residue 6 serves as a neutral spacer. Thus, the main features responsible for the high delta-opioid selectivity of dermenkephalin are electrostatic repulsions with the mu-opioid receptor, additional hydrophobic interactions with the delta-opioid receptor and folding of the C-terminal domain.
Charpentier
S
S
Laboratoire de Bioactivation des Peptides, Institut Jacques Monod, Université Paris, France.
Sagan
S
S
Naim
M
M
Delfour
A
A
Nicolas
P
P
D000595:Amino Acid Sequence; D000818:Animals; D002531:Cerebellum / Q000378:metabolism; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D017465:Receptors, Opioid, delta; C059567:deltorphin