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Accueil > Publications > Recherche par années > Années 1990 > 1994

Charpentier, S ; Sagan, S ; Naim, M ; Delfour, A ; Nicolas, P

Mechanisms of d-opioid receptor selection by the address domain of dermenkephalin

European Journal of Pharmacology-Molecular Pharmacology Section 266 (2) 175-180

par Administrateur - publié le

Abstract :

Dermenkephalin (Tyr-D-Met-Phe-His-Leu-Met-AspNH(2)) is a highly potent and selective d-opioid peptide isolated from frog skin. It was recently 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 towards the d-opioid receptor. In order to investigate the role played by residues 4, 5 and 6 in this ’d address’, we synthesized and evaluated 20 new analogues for their ability to displace tritiated ligands from mu- and d-opioid sites. Results showed that position 4 of dermenkephalin contributes to 6 selectivity independently of d-opioid receptor binding by preventing a high affinity mu binding. Position 5 requires a hydrophobic side chain to enhance d affinity. A high d 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 d-opioid selectivity of dermenkephalin are electrostatic repulsions with the mu-opioid receptor, additional hydrophobic interactions with the d-opioid receptor and folding of the C-terminal domain.