Open AccessConversion of Enkephalin and Dermorphin into δ‐Selective Opioid Antagonists by Single‐Residue Substitution
Author(s) -
Tancredi Teodorico,
Salvadori Severo,
Amodeo Pietro,
Picone Delia,
Lazarus Lawrence H.,
Bryant Sharon D.,
Guerrini Remo,
Marzola Giuliano,
Temussi Piero A.
Publication year - 1994
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1111/j.1432-1033.1994.tb20017.x
Subject(s) - dermorphin , naltrindole , chemistry , stereochemistry , opioid peptide , agonist , enkephalin , morpholine , peptide , moiety , opioid , opioid receptor , receptor , medicinal chemistry , biochemistry
The properties of di‐ and tri‐peptides containing 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid (Tic) in second position suggest that the message domain of opioid peptides can be composed of only two residues [Temussi, P. A., Salvadori, S., Amodeo, P., Guerrini, R., Tomatis, R., Lazarus, L. H., Picone, D. & Tancredi, T. (1994) Biochem. Biophys. Res. Commun. 198 , 933–9391. As a crucial test of the possibility that the Tyr‐Tic segment be a message domain in longer peptide sequences, we have inserted it in the sequences of two typical opioid peptides: [Leu]enkephalin, a non‐selective agonist, and dermorphin, a selective μ agonist. Here we report the synthesis and biological activity of [ l ‐Tic 2 ]enkephalin, [ l ‐Tic 2 ]dermorphin, [ l ‐Tic 2 ]dermorphin carboxylic acid and [ d ‐Tic 2 ]dermorphin: all [ l ‐Tic 2 ]peptides were converted from agonists to δ‐selective antagonists. The NMR conformational study in a dimethylsulfoxide/water cryoprotective mixture at low temperature shows diagnostic side‐chainside‐chain NOEs in the spectra of all [ l ‐Tic 2 ]peptides and hints that the 90° arrangement of the the two aromatic rings found in the cis‐Tyr‐ l ‐Tic moiety, typical of N ‐methyl naltrindole and other δ‐selective opiate antagonists, is responsible for the antagonist activity of all these peptides.