Enkephalin degradation

Several enzymes, none of which are completely specific for the enkephalins, are known to cleave Leu- and Met-enkephalin at various peptide bonds. The main enzymes that degrade enkephalin are 2inc metaHopeptidases. The first enkephalin-degrading enzyme to be identified, an aminopeptidase which cleaves the amino terminal Tyr-Gly bond (179), has been shown to be aminopeptidase-N (APN) (180). It is a cytoplasmic enzyme which is uniformly distributed throughout the brain. The increased analgesic activity of synthetic enkephalins substituted by D-amino acids at position 2, eg,... 

Tariot PN, Cohen RM, Welkowitz JA, et al Multiple-dose arecohne infusions in Alzheimer s disease. Arch Gen Psychiatry 45 901-905, 1988 Taylor AE, Saint-Cyr JA, Lang AE Frontal lobe dysfunction in Parkinson s disease the cortical focus of neostriatal outflow. Brain 109 845-883, 1986 Taylor DP, Smith DW, Hyslop DK, et al Receptor binding and atypical antidepressant drug discovery, in Receptor Binding in Drug Research. Edited by O Brien RA. New York, Marcel Dekker, 1986, pp 151-165 Tejedor-Real P, Mico JA, Maldonado R, et al Effect of mixed (RB 38A) and selective (RB 38B) inhibitors of enkephalin degrading enzymes on a model of depression in the rat. Biol Psychiatry 34 100-107, 1993... 

GASTROINTESTINAL EFFECTS OF ENKEPHALIN DEGRADING ENZYME INHIBITORS ROLE OF DELTA OPIOID RECEPTOR IN THE ANTISECRETORY EFFECT OF TIORFAN... 

On the other hand, a number of studies have shown that morphine and opioid peptides could have cardioprotective effects toward ischemic processes and may be able to reduce the size of infarct [72,73]. These effects seem to involve the activation of delta opioid receptors, the localization of which remains unknown. In addition, enkephalin-degrading enzyme inhibitors, such as acetorphan and, particularly, RB 101, have also been demonstrated to decrease the susceptibility to the arrhythmogenic action of epinephrine. Thus RB 101 completely prevented the ventricular tachycardia, fibrillation, and repetitive ventricular extrasystoles induced by epinephrine (Maslov et al., unpublished data). These effects were reversed by the selective delta antagonist ICI 174,864. 

Elastase, inhibition, 31 (1994) 59 Electron spin resonance, 12 (1975) 191 Electrophysiological (Class III) agents for arrhythmia, 29 (1992) 65 Endorphins, 17 (1980) 1 Endothelin inhibition, 31 (1994) 371 Enkephalin-degrading enzymes, 30 (1993)... 

Metabolism - It has been shown that aminopeptldase-induced enkephalin degradation proceeds at the same rate whether or not the peptide is bound to... 

Patel, A., Smith, H.J. and Sewell, R.D. (1993) Inhibitors of enkephalin-degrading enzymes as potential therapeutic agents. Prog. Med. Chem. 30 327-378. 

Specific peptidase and protease systems which involve Mn(II) include thrombin limited-proteolysis of prothrombin [122], insulin protease [123], enkephalin-degrading amino-peptidase [124], camosinase [125,129], ki-ninase [127], and trypsin activation [128]. A metalIo(Mn)-protease is involved in the processing of mitochondrial precursor proteins [130]. Several aminopeptidases are also specifically manganese-dependent, namely Leu-aminopeptidase [131] and prolidase or C-terminal proline dipeptidase [132-135]. Other systems that hydrolyze linear and cyclic G-N bonds include various amino-acylases, deacetylases, amidases and methylene-... 

Inhibitors of Enkephalin-degrading Enzymes as Potential Therapeutic Agents... 

ENKEPHALIN-DEGRADING ENZYMES AND THEIR INHIBITORS Assessment of enkephalin-degrading enzymes as enkephalin neuropeptidases Aminopeptidases... 

Combined inhibitors of enkephalin-degrading enzymes Prodrugs... 

Both enkephalinase and membrane-bound aminopeptidases, particularly aminopeptidase M, are strong candidates as brain enkephalin-degrading neuropeptidases and fulfil the criteria laid down for this role [26]. The significance of aminopeptidase Mil has been insufficiently investigated for the enzyme to be disregarded as an enkephalin neuropeptidase. The role of DAP appears to be minor, at least in the CNS, although a peripheral role may be indicated [37], ACE is unlikely to be involved in deactivation of endogenously released enkephalin. 

The dipeptide Phe-Phe is a selective inhibitor of DAP [114] and has been used as a basis for the development of more potent combined inhibitors of enkephalin-degrading enzymes [36]. 

Hydroxamic acid derivatives have been reported to inhibit thermolysin, enkephalinase and enkephalin-degrading aminopeptidases. Benzyloxycar-bonyl amino acid hydroxamates (Figure 6.9A) were reported to be potent inhibitors of both enkephalinase and soluble enkephalin-degrading amino-peptidase. Other hydroxamic acid derivatives also act as inhibitors of enkephalinase and membrane-bound enkephalin degrading aminopeptidase [68] (Figure 6.9B). 

Figure 6.9. Combined inhibitors of enkephalin degrading enzymes. ENK (enkephalinase). AP (aminopeptidases), APM, (aminopeptidase M), DAP (dipeptidylaminopeptidase). D,R,S (stereochemical configuration), ° (membrane-bound aminopeptidase). (soluble aminopeptidase).

The pharmacology of enkephalin-degrading enzyme inhibitors should parallel that of the enkephalins if inhibitors increase the level of endogenous enkephalins. However, other peptides and hormones such as atrial natriuretic peptide and Substance P are cleaved by enkephalinase (membrane metalloendopeptidase). Enkephalinase inhibitors may thus have a potential therapeutic role in areas which are unrelated to the actions of the enkephalins. 

The majority of the in vivo effects of enkephalin-degrading enzyme inhibitors have been investigated either by co-administration with an enkephalin analogue or by introduction of an external stress factor to activate the endogenous enkephalinergic system. 

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. 

Other factors such as difficulty in quantification and thus measurement of processes involved in pain and mental illness have also hindered the process of establishing any therapeutic role of enkephalin-degrading enzyme inhibitors in these conditions. However, they have proved to be useful pharmacological tools . The most likely therapeutic role at present appears to be in the treatment of cardiovascular disorders. 

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