Dermorphin analogs

Conformationally Constrained Analogs. Dermorphin analogs containing a local constraint were prepared by incorporation of a dipeptide mimetic in place of Phe -Gly". The Aba -Gly" (see Fig. 7.43) analog of dermorphin retains high affinity at [x receptors and potency in the GPI, whereas this structural modification increases S-receptor affinity and potency in the MVD 17- to 25-fold (892). A number of heterocycles are also tolerated as bond replacements for the Phe -Gly" peptide bond (893). 

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. 

Amino acid substitutions have been examined in every position of dermorphin (see Ref 663 for a review). An alanine scan of the peptide indicated that substitutions in positions 4, 6, and 7 are well tolerated, whereas substitution particularly in positions 1 or 2, but also in positions 3 or 5, results in large decreases in potency in the GPI (877). A o-amino acid in position 2 is important for activity, and the L-Ala peptide is virtually inactive (<0.1% the potency of dermorphin). Tetrapeptide analogs containing D-methionine sulfoxide in position 2 are also potent p-selective agonists (878). 

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). 

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