Retro-thiorphan

Roderick, S. L., Fournie-Zaluski, M. C., Roques, B. P, Matthews, B. W. Thiorphan and retro-thiorphan display equivalent interactions when bound to crystalline thermolysin. Biochemistry 1989, 28, 1493-1497. 

The reversal of the peptidic functional groups is often used in peptide chemistry. The retropeptides obtained are generally more resistant to enzymatic attacks (Fig. 13.17). For thiorphan and retro-thiorphan an identical binding mode to the zinc protease thermolysin was demonstrated. Similar inhibition values for thermo-lysin and neutral endopeptidase were observed, whereas, for another zinc protease, angiotensin converting enzyme (ACE), noticeable differences for inhibition were found (Fig. 13.20). 

Fig. 13.20 Inhibition values of thiorphan and retro-thiorphan for three zinc proteases.

Figure 3.1 Thiorphan and retro-thiorphan show similar biological activity against thermolysin and NEP24.11, but their activities are significantly different against ACE. The exam pie demonstrates that molecular similarity depends on the structure of the target protein [15],...

Influence of the peptide bond between AAj and AA2 residues. iV-methylation of the peptide link in the dipeptides Phe-Gly, Phe-Ala or Phe-Leu, leads to a 100-fold reduction in inhibitory activity indicating that the amide group is hydrogen bonded to the active site of the enzyme [78]. Support for this now comes from the observation that a retro-peptide bond in Phe-Ala reduces inhibitory activity 10-fold. Whereas there is only a modest loss of inhibitory activity in (i )-thiorphan (thiol analogue of the dipeptide Tyr-Gly), there is a 100-fold loss in activity in the (.S)-isomer of retrothiorphan (see Table 6.6) [90]. 

Table 6.6. EFFECT OF RETRO-INVERSION ON THE ENKEPHALINASE INHIBITORY ACTIVITY OF THIORPHAN AND RETROTHIORPHAN [90]...

Some enkephalin degrading enzyme inhibitors which exhibit potent enzyme inhibitory activity in vitro, are only active in nociceptive tests in vivo, when administered icv. A discrepancy exists, for some compounds, between enzyme inhibitory potency in vitro and antinociceptive effects observed in vivo. For example both the (R) and (S) enantiomers of thiorphan exhibit similar potency in vitro, yet the antinociceptive effect obtained in vivo is greater for the (/ )-isomer than the (S)-isomer [124]. Similarly, the retrokelatorphan derivative (Fig 6.10B) [117], exhibits inhibitory potency for enkephalinase, DAP and aminopeptidase M, in a range similar to that of kelatorphan [125]. However, the antinociceptive effects of retrohydroxamates are significantly weaker than kelatorphan, an effect which cannot be explained in terms of metabolic stability as retro-inversion of an amide bond tends to protect it from hydrolysis. 

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