Amino acid composition and sequence of dermorphin, a novel opiate-like peptide from the skin of Phyllomedusa sauvagei

This study, published by Pietro Montecucchi and the legendary Italian pharmacologist Vittorio Erspamer, marked the discovery and structural characterization of dermorphin — one of the most potent opioid peptides ever isolated from a natural source. The work was carried out using methanol extracts from the skin of the Amazonian frog Phyllomedusa sauvagei, within Erspamer's program that systematically screened South American amphibian skin secretions for bioactive compounds.

The authors established that dermorphin is a heptapeptide with the sequence H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH₂. The most unexpected discovery was the presence of D-alanine at position 2 — an extremely rare structural feature in vertebrate peptides, since ribosomes exclusively synthesize proteins from L-amino acids. This D-alanine is generated by a specific post-translational isomerase and is responsible for dermorphin's resistance to enzymatic degradation.

Preliminary pharmacological experiments showed that dermorphin possesses exceptionally intense and long-lasting central and peripheral opioid actions, with analgesic potency superior to that of known enkephalins, β-endorphin, and even morphine. The peptide bound with high affinity and selectivity to μ-opioid receptors, in contrast to enkephalins (predominantly delta).

This work was historically fundamental for (1) revolutionizing the conception of vertebrate biochemistry, by demonstrating that peptides with D-amino acids exist in animal nature, and (2) inaugurating a new class of peptide opioids (dermorphins and deltorphins), with applications in pain research, neuroscience, and pharmaceutical development. The name "dermorphin" was coined by the authors combining derm- (skin) and -morphine (morpho + opioid).