Amphibian skin, opioid peptide

The unique feature of these amphibian skin opioid peptides is the sequence between the important aromatic residues. In contrast to the enkephalins and other mammalian opioid peptides that contain the Gly-Gly dipeptide sequence between Tyr and Phe, the amphibian opioid peptides contain a single D-aminoacid (see Fig. 7.41), which apparently arises from a post-translational conversion of the L-amino acid to its d isomer (665). The identification of these unusual opioid peptides expanded our understanding of the structural requirements for interaction with opioid receptors and provided new lead compounds for further modification (see Sections 6.5.1 and... 

Kreil, G., Barra, D., Simmaco, M., Erspamer, V., Erspamer, G. F., Negri, L., Severini, C., Corsi, R., Melchiorri, P. Deltorphin, a novel amphibian skin peptide with high selectivity and affinity for S opioid receptors, Eur. J. Pharmacol. 1989, 162, 123-128. 

We started out our studies on amphibian opioid peptides in the wake of the explosion of research on mammalian endogenous ligands for opiate receptors. We asked ourselves whether the never disappointing amphibian skin contained related molecules. The question was reasonably posed in the light of the outcome of our previous, yearlong research showing that amphibian skin peptides often had counterparts in mammalian CNS and gastrointestinal tract [1]. 

Similar to mammalian prohormones, all opioid peptides in amphibian skin precursors are flanked by paired dibasic amino acids (Lys-Arg). Moreover, the precursor sequence contains an additional Gly residue at its carboxyl terminus this extra residue is required for the carboxamidation of the mature heptapeptide [20]. 

Based on their finding amphibian skin peptides, which were counterparts to other mammalian bioactive peptides, Erspamer and coworkers examined amphibian skin for opioid peptides (see Ref 663 for a review). This led first to the isolation and characterization of dermorphin (212, Fig. 7.41), which is a ja-se-lective peptide (see Table 7.13), from the skin of South American Phyllemedusinae hylid frogs in the early 1980s (664). Inspection of the sequence of one of the cloned cDNAs for the precursor of dermorphin suggested the existence of another heptapeptide with a similar iV-terminal sequence (665). This then led to the isolation of deltorphin (alsocalled dermenkephalin or deltorphin A, 213, Fig. 7.41), the first S-selective amphibian opioid peptide, from these frogs (666, 667). Synthesis confirmed that the amino acid in position 2 of deltorphin was o-methionine rather than L-methionine (666,668, 669). Two additional peptides [o-Ala ldeltorphin I (also referred to as deltorphin C, 214, Fig. 7.41) and [o-Ala ]deltorphin II (also referred to as deltorphin B, 25, Fig. 7.5) were subsequently discovered (106) which exhibited even greater 8-receptor affinity and exceptional selectivity... 

Table 7.13 Opioid Receptor Affinities and Opioid Activity in the GPI and MVD of Peptides from Amphibian Skin ...

Heyl DL, Schullery SE (1997) Developments in the structure-activity relationships for the delta-selective opioid peptides of amphibian skin. Curr Med Chem 4 117-150... 

The opioid peptides stem from a large precursor molecule in which several copies of the enkephalins are present, the ratio between Met-enkephalin and Leu-enkephalin being 6 1 [39]. The same precursor, pro-opiocortin, also contains a modified form of the enkephalin sequence in which the N-terminal tyrosine is present as the sulfate ester [40]. This kind of post-translational change has been discussed in connection with gastrin, cholecystokinin and caerulein (p. 165). The last mentioned peptide prompts us to recall dermorphin (p. 186), an opioid peptide found in the skin of an amphibian. 

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