CONVERSION OF ENKEPHALIN AND DERMORPHIN INTO DELTA-SELECTIVE OPIOID ANTAGONISTS BY SINGLE-RESIDUE SUBSTITUTION

The properties of di- and tri-peptides containing 1,2,3,4-tetrahydrois oquinoline-3-carboxylic acid (Tic) in second position suggest that the message domain of opioid peptides can be composed of only two residue s [Temussi, P. A., Salvadori, S., Amodeo, P., Guerrini, R., Tomatis, R ., Lazarus, L. H., Picone, D. gr Tancredi, T. (1994) Biochem. Biophys. Res. Commun. 198, 933-939]. As a crucial test of the possibility that the Sr-Tic segment be a message domain in longer peptide sequences, w e have inserted it in the sequences of two typical opioid peptides: [L eu]enkephalin, a non-selective agonist, and dermorphin, a selective mu agonist. Here we report the synthesis and biological activity of [L-T ic(2)]enkephalin, [L-Tic(2)]dermorphin, [L-Tic(2)]dermorphin carboxyli c acid and [D-Tic(2)]dermorphin: all [L-Tic(2)]peptides were converted from agonists to delta-selective antagonists. The NMR conformational study in a dimethylsulfoxide/water cryoprotective mixture at low tempe rature shows diagnostic side-chain - side-chain NOEs in the spectra of all [L-Tic(2)]peptides and hints that the 90 degrees arrangement of t he the two aromatic rings found in the cis-Tyr-L-Tic moiety, typical o f N-methyl naltrindole and other delta-selective opiate antagonists, i s responsible for the antagonist activity of all these peptides.