DERMORPHIN

Discovery

Between the 1960s and 1980s, many active peptides were identified in the skin of the South American leapfrog belonging to the genus Phyllomedusa. Dermorphin (DM) was isolated from the skin of P. sauvagei as a potent opiate-like peptide.1 At present, seven endogenous analogs (DM, [Hyp6 ]DM, [Lys7 ] DM, [Lys7 ]DM-OH, [Trp4 , Ans7 ]DM, [Trp4 ,Ans7 ]DM-OH, and [Trp4 ,Ans5 ]DM(1- 5)-OH) have been identified. DM is not found in mammals.

Structure

DM consists of seven aa residueswith an amidated serine at the C-terminus. DM does not contain the common N-terminal sequence for the traditional endogenous opioid peptides (Tyr-Gly-Gly-Phe), and its sequence is completely different from that of the endomorphins, which were identified as endogenous μ-opioid peptides that also do not contain the common sequence. Interestingly, DM contains D-Alanine (D-isomer amino acid) in its sequence. H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2. Mr 803. Soluble in water (up to 2mg/mL) and acetonitrile. Dermorphin should be stored at -20°C. It is also hygroscopic and must be protected from light.

Gene, mRNA, and precursor

DM and its endogenous analogs are synthesized from a precursor that contains multiple copies of the progenitor sequence. In these cloned cDNAs, the alanine codon GCG occurs at the position where D-alanine is present in the end product, suggesting a posttranslational conversion of an L-amino acid to its D-isomer carried out by an amino acid isomerase.

Receptors

DM shows a very high affinity for μ-opioid receptors and a low affinity for δ-opioid receptors, which are subtypes of opioid receptors belonging to the GPCR superfamily.

Clinical implications

DM produces a long-lasting antinociceptive activity, with more than 200 times the potency of morphine.6- [Lys⁷]DM also exhibits a long-lasting antinociceptive potency exceeding that of morphine by 25- to 30-fold by peripheral administration with high penetration into the blood-brain barrier. Within synthetic DM analogs, some of the N-terminal tetrapeptide analogs containing D-Arg² have antinociceptive profiles that are distinct from those of traditional μ-opioid receptor agonists. Preliminary clinical studies found that the analgesic effect of intrathecal DM (20μg) was profound and lasts significantly longer (43.41±1.64 h) than intrathecal morphine (500μg, 34.45±2.35 h) or routine pentazocine therapy (30mg, 10.79±2.23 h). However, DM was never again introduced in the clinical setting. A few studies have reported the effects of DM on endocrine systems in humans. Intravenous infusion (5.5μg/kg per min for 30min) of DM significantly increased the plasma levels of prolactin, growth hormone, thyrotropin, and renin activity, but decreased the plasma levels of cortisol. In fertile women, DM (5.5μg/kg per min for 30min) decreased the plasma levels of the luteinizing hormone, but not of the follicle-stimulating hormone.

Description

A heptapeptide isolated from amphibian skin, dermorphin, containing D-alanine (a D-isomer amino acid) and shows very high selectivity for μ-opioid receptors.