Deltorphins: a family of naturally occurring peptides with high affinity and selectivity for delta opioid binding sites.

Abstract

Deltorphins are endogenous linear heptapeptides, isolated from skin extracts of frogs belonging to the genus PhyUomedusa, that have a higher affinity and selectivity for 6 opioid binding sites than any other natural compound known. Two deltorphins with the sequence Tyr-Ala-Phe-Asp(or Glu)-Val-Val-Gly-NH2 have been isolated from skin extracts of PhyUomedusa bicolor. The alanine in position 2 is in the D configuration. These peptides, deltorphins I and II, show an even higher affinity for 6 receptors than the previously characterized deltorphin, which contains D-methionine as the second amino acid. These peptides show some similarity to another constituent of Phylomedusa skin, dermorphin, which is highly selective for ,u-opioid receptors. These peptides all have the N-terminal sequence Tyr-D-Xaa-Phe, where D-Xaa is either D-alanine or D-methionine. While this structure seems to be capable of activating both pA and 6 opioid receptors, differences in the C-terminal regions of these peptides are probably responsible for the observed high receptor selectivity of dermorphin and deltorphin.The endogenous opioid ligands isolated from vertebrate brain show little selectivity toward the different types of opioid receptors. Peptides isolated from amphibian skin appear to be more selective. In 1981 Montecucchi et al. (1) extracted from the skin of the Argentinian frog Phyllomedusa sauvagei a heptapeptide named dermorphin, which preferentially binds to A-type opioid receptors (2). By recombinant DNA techniques, it was demonstrated that dermorphin, like numerous other peptides, is derived in multiple copies from larger precursors. In addition, from inspection of the sequence of one of the cloned cDNAs for these precursors, the existence of another heptapeptide with an N-terminal region similar to that of dermorphin was predicted (3). We recently succeeded in isolating small quantities of this peptide from the skin ofP. sauvagei and named it deltorphin, because of its high affinity and selectivity for the 8 opioid binding site (4). Both dermorphin and deltorphin contain a D amino acid (D-alanine and D-methionine, respectively) as the second amino acid. In the cloned cDNAs, codons for the corresponding L amino acids-i.e., GCG for alanine and ATG for methionine-were found at these positions. This characteristic suggested that the processing of these peptides includes a reaction whereby an L amino acid residue is converted to its D isomer within peptide linkage (3). Here we describe the isolation of two other heptapeptides from the skin of Phyllomedusa bicolor, which show an affinity and selectivity for 8 opioid receptors several times higher than that of deltorphin and the cyclic enkephalin derivative enkephalin (DPDPE, where D-Pen is D-penicillamine) (5). Once again, these peptides contain a D-alanine residue in the second position and share with dermorphin and deltorphin the N-terminal sequence Tyr-D-Xaa-Phe. We refer to these peptides, which differ by the presence of an aspartic or glutamic residue in position 4,...

Frog secretions and hunting magic in the upper Amazon: identification of a peptide that interacts with an adenosine receptor.

“…These include high levels of phyllocaerulein, phyllokinin, and phyllomedusin and moderate levels of sauvagine. Small amounts of deltorphins, a class of opioid agonists selective for 8 receptors, also are present (5). We initially felt it unlikely that either the vasoactive peptides or the small amounts of deltorphins would account for effects on humans attributed to secretions from P. bicolor.…”

Synergy between receptors mediates adenosine release from spinal cord synaptosomes

“…and Cys4]deltorphin (lOOO-fold-selective) have higher selectivity for the 6-opioid receptor compared to the p-opioid receptor site (Mosberg et al, 1983;Erspamer et al, 1989). The degree of enhancement of adenosine release by each p-opioid receptor agonist varied for the two Sopioid receptor ligands.…”

Search of the human proteome for endomorphin-1 and endomorphin-2 precursor proteins

“…In addition, atypical peptides have been isolated from frog skin that are mu receptor-selective (the dermorphins, Broccardo et al, 1981) or delta receptor-selective (the deltorphins, Erspamer et al, 1989). The distinctive feature of the amphibian peptides with opioid-like activity is the presence of D-amino acids at the second position of their amino termini, Tyr-D-Xaa-Phe (reviewed in Negri et al, 2000).…”