New insights on the mu/delta selectivity of opioid peptides: conformational analysis of deltorphin analogues

TANCREDI T;TEMUSSI PA;PICONE D;AMODEO P;TOMATIS R;SALVADORI S;MARASTONI M;SANTAGADA V;BALBONI, GIANFRANCO

1991-01-01

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Abstract

The message domain of dermorphin (Tyr-D-Ala-Phe), a natural μ-opioid heptapeptide, has long been considered the main cause of the high μ selectivity of this peptide and of its analogues. The recent discovery, in the skin of Phyllomedusa sauvagei (i.e., the same natural source of dermorphin) and of Phyllomedusa bicolorof deltorphins, challenges this belief. Deltorphins, in fact, are three heptapeptides characterized by a message domain typical of μ-selective peptides, but endowed of an extremely high δ selectivity, the highest of all natural opioid peptides. A conformational analysis of dermorphin and deltorphins, based on nmr studies in DMSO and cryoprotective mixtures and internal energy calculations, showed that the enormous differences in receptor selectivity can be interpreted on the basis of receptor models for μ and δ opioids that recognize the same β-turn in the N-terminal part, but discriminate for the conformation and polarity of the C-terminal part. Here we present the synthesis, biological activity, and conformational analysis in solution of three deltorphin analogues with very similar constitution, but with different net charge, different location of negative residues, or even without negative residues, which confirm these hypotheses and show that His4 can play a specific structural role.