Dermorphins

H-Tyr-D-Ala-Pile-Asp-Val-Val-Gly-NH2 (D-Ala -deltorpliiu I) and H-Tyr-D-Ala-Plie-Glu-Val-Val-Gly-NH2 (D-Ala -deltorpliiu II) display greater 5-selectivity than DPDPE owiag to their higher 5-receptor affinity (96). These compounds both contain the same N-terminal tripeptide sequence as the. -selective dermorphins, which underscores the importance of the C-terminal tetrapeptide sequence in conferring 5-selectivity. 

Table 1 Opioid Receptor Affinities of Cyclic Dermorphin Analogues ... 

The multiple conformational restriction of dermorphin-related tet-rapeptide analogues that was performed represents a rational design of opioid peptidomimetics characterized by a high degree of structural rigid-ification. This is indicated by the fact that the p-selective agonist H-Hat-D-Orn-Aic-Glu-NH2 contains only two freely rotatable bonds, whereas there are 14 freely rotatable bonds in [Leu5]enkephalin. 

Montecucchi PC, de Castiglione R, Piani S, Gozzini L, Erspamer V. Amino acid composition and sequence of dermorphin, a novel opiate-like peptide from the skin of Phyllomedusa sauvagei. Int J Peptide Protein Res 1981 17 275-283. 

Wilkes BC, Schiller PW. Conformation-activity relationships of cyclic dermorphin analogues. Biopolymers 1990 29 89-95. 

Other examples include dermorphin, which is cleaved at the 4,5-bond in rat brain homogenates. Whereas the metabolic stability of its [4t/t5,CH2-S] analogue was increased 14-fold, that of the 3t// CH2-S] analogue was increased 7-fold. 

Figure 2.8. Scheme of a chimeric peptide with examples for each of the distinct domains. 0X26, anti-rat transferrin receptor monoclonal antibody (mAh) 84-15, anti-human insulin receptor mAh cHSA, cationized human serum albumin VIP, vasoactive intestinal polypeptide DALDA, dermorphin analogue NGF, nerve growth factor BDNF, brain-derived neurotrophic factor PNA, peptide nucleic acid (3-gal, (3-galactosidase. 

Alternatively, if the dehydroamino acid is C-terminal or is central in the peptide chain, then the oxazolone precursor to the dehydropeptide must be in position two in order to apply this methodology (Scheme 7.165). The requisite unsaturated 5(4//)-oxazolone intermediate 518 is obtained from the appropriate precursors following standard cyclization procedures and avoiding experimental conditions that would epimerize the chiral center. This methodology has been applied to access analogues of important peptides including dehydroaspartame, somatostatin, and dermorphin. In these cases, a dehydroamino acid was incorporated into the peptide backbone to study the relationship between conformational restriction and biological properties of the modified peptide. 

Fluorination of the aromatic ring (or in some cases also the introduction of the 18F isotope) in some bioactivc compounds has been successfully performed (e.g., fluoroantipyrine. fluoro-dopa).21 24,35 Regiospecific fluorination of the tyrosine ring of the A-terminal tetrapeptide amide (Tyr — n-Ala — Phe — Gly-NH2) sequence of the opiate peptide dermorphin was achieved in good yield by reaction with acetyl hypofluoritc to give 28.21... 

DAMME [D-Ala2,MePhe4,Met(0)-ol5]enkephalin [D-Me. Pro enkephalinamide [D-Ala2]deltorphin I [D-Ala2]deltorphin II [D-Ala2]dermorphin... 

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-... 

The first peptide family of amphibian opiates was discovered in 1981 and named dermorphins [2,3], Until the discovery of mammalian endomor-phins by Zadina et al. [4], these peptides represented the most potent and selective mu opiate receptor agonists identified in living organisms. Nine years later, deltorphins were discovered in the amphibian skin. These peptides are still the most potent and selective delta opiate agonists available today [5]. 

The screening of a cDNA library prepared from the skin of Ph. sauvagei established the amino acid sequence of several dermorphin precursors. The... 

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