Peptides opioid peptide dermorphin

Despite a common N-terminal tripeptide (Tyr-D-Xaa-Phe), the two groups of opioid peptides, dermorphins and deltorphins, differ enormously in receptor selectivities but bind to their own receptors with similar affinities. The N-terminal domain contains the minimum sequence essential for binding to opioid receptors whereas the C-terminal domain contains the address requisites for receptor selectivity. 

Mizoguchi, H., Watanabe, C., Watanabe, H., Moriyama, K., Sato, B., Ohwada, K., Yonezawa, A., Sakurada, T., and Sakurada, S. (2007). Involvement of endogenous opioid peptides in the antinociception induced by the novel dermorphin tetrapeptide analog amidino-TAPA. Eur. J. Pharmacol. 560, 150-159. 

In addition to in vitro cell models, opioid agonists could induce the rapid endocytosis of the receptor in organo cultures or primary neuronal cultures, and also neurons in vivo. Treatment of longitudinal muscle-myenteric plexus preparation or the primary hippocampal neuron cultures with DAMGO resulted in internalization of the mu opioid receptor [146,147]. Similar observation was obtained with fluorescently labeled opioid peptides Fluo-dermorphin and Fluo-deltorphin [148]. Within 15 min of an intra-peritoneal injection of etorphine, mu opioid receptor immunoreactivity was observed in the endosomal structures of the myenteric neurons of guinea pig ileum [149]. Again, rapid clustering of a spliced variant of mu opioid receptor MOR-1C was observed in the lateral septum of the mouse after intracere-... 

Endorphins, Enkephalins, Dynorphin, and Dermorphin (Opioid Peptides)... 

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... 

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. 

D PASS approach was extensively exploited by Potrzebowski group in the course of investigation of the structural and dynamical properties of the signal sequences of the deltorphin and dermorphin—naturally occurring opioid peptides. This experiment was applied for the structure and dynamics elucidation of Tyr-D-Ala-Phe [92] and investigation the influence of hydratation on the changes in the dynamical properties of the Tyr-L-Ala-Phe tripeptides [93]. 

Glycopeptide derivatives of the p-and 5-opioid receptor agonists deltorphin and dermorphin have been examined for in vivo activity [187,188]. Peptide agonists themselves generally only reach the central nervous system in low quantities, mainly due to their inability to cross the... 

Substitutions for Gly" are well tolerated, particularly in the tetrapeptide derivatives. Sarcosine (NMeGly, Sar) at position 4 in tetrapeptide derivatives enhances opioid activity in antinociceptive assays (879). Substitution of Phe in position 4 of the tetrapeptide amide yields the dermorphin/enkephalin hybrid TAPP (T -D-Ala-Phe-PheNHa) (831), which is a potent p-selective agonist (see Table 7.18). This peptide can also be considered an analog of en-domorphin-2, although TAPP was synthesized several years before the discovery of the endo-... 

Incorporation of o-Arg in position 2 of dermorphin and tetrapeptide analogs yields peptides that are potent opioids in antinociceptive assays in mice (879,882). The tetrapeptide derivative Tyr-D-Arg-Phe-Sar (TAPS)is a potent opioid in antinociceptive assays and causes respiratory stimulation, rather than respiratory depression, that is antagonized by naloxonazine (883) TAPS also antagonizes the respiratory depression caused by dermorphin. On the basis of these results TAPS has been postulated to be a p-i agonist and a antagonist in vivo (883). In contrast, incorporation of L-Tic in position 2 of dermorphin converts the peptide to a 6-receptor antagonist (884). 

Peptides with opioid activity have been isolated from sources other than mammalian brain. The heptapeptide p-casomorphin (Tyr-Pro-Phe-Pro-Gly-Pro-lle), found in cow s milk, is a p opioid agonist (11). Dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), a p-selective peptide isolated from the skin of South American frogs, is approximately 100-fold more potent than morphine in in vitro tests (12). 

Negri L, Erspamer GF, Severinl C, et al. Dermorphin-related peptides from the skin of Phyllomedusa bicolor and their amidated analogues activate two p opioid receptor subtypes that modulate antinociceptlon and catalepsy In the rat. Proc Natl Acad Sci USA 1992 89 7203-7207. 

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