Enkephalinase

Enkalon Enkastat Enkatherm Enkephalin analogues Enkephalinase Enkephalinase A Enkephalins... 

Neurokinin effects are terrninated by proteolysis. In vitro acetylcholinesterase (ACE) and enkephalinase can hydrolyze substance P. However, there appears to be no clear evidence that either acetylcholinesterase or ACE limit the actions of released substance P. Enkephalinase inhibitors, eg, thiorphan, can augment substance P release or action in some systems but the distribution of enkephalinase in the brain does not precisely mirror that of substance P. There appears to be a substance P-selective enzyme in brain and spinal cord. 

R = R = H), the first reported enkephalinase inhibitor, produced analgesia in post-myelography headache pain, but not in shock-induced pain (38). There was no tolerance or dependence observed. 

Borson, D.B., Malfroy, B., Gold, M., Ramachandran, J. and Nadel, J.A. (1986). Taehykinins inhibit enkephalinase activity from trachea and lung of ferrets. Physiologist 29, 174A. 

Yeadon, M., Wilkinson, D. and Payne, A.N. (1990). Ozone induces bronchial hyperresponsiveness to inhaled substance P through functional inhibition of enkephalinase. Br. J. Pharmacol. 99, 191P. 

Roge J, Baumer P, Berard H, Schwartz JC, Lecomte JM The enkephalinase inhibitor, acetorphan, in acute diarrhoea. A doubleblind, controlled clinical trial versus loperamide. Scand J Gastroenterol 1993 28 352-354. 

MA 9 Families of exo- and endopeptidases (including several aminopeptidases in family Ml, and enkephalinase in family M13) Zn2+ Bound to //w-Glu-Xaa-Xaa-His (HEXXH motif) a/f ... 

Neprilysin (enkephalinase, Endopeptidase-24.11, neutral endopeptidase, NEP, EC 3.4.24.11) bears considerable resemblance to other zinc-containing metallopeptidases it is an oligopeptidase that hydrolyzes enkephalins and a range of other active peptides. Enkephalins are endogenous ligands of opiate receptors, and the prolongation of their action via inhibition of enkephalinase... 

Fig. 3.13. The 3D structure of neprilysin (enkephalinase, EC 3.4.24.11) obtained from ldmt.pdb [79]. This structure was determined for the enkephal-inase-phosphoramidon complex, but the inhibitor has been removed to unmask the catalytic center, a) Structure of the enzyme, with the Glu and the two His residues of the HEXXH zinc-binding motif shown in blue, b) Zoom on the catalytic center, revealing the spatial arrangement of the zinc-binding residues.

J. C. Schwartz, Enkephalinase Inhibitors as Drugs , in Design of Enzyme Inhibitors as Drugs , Eds. M. Sandler, H. J. Smith, Oxford University Press, Oxford, 1989, p. 206-226. 

D. M. Lambert, F. Mergen, C. F. Berens, J. H. Poupaert, P. Dumont, Synthesis and Pharmacological Properties of 2-[S-Acetylthiophan]-l,3-diacylaminopropan-2-ol Derivatives as Chimeric Lipid Drug Carriers Containing an Enkephalinase Inhibitor , Pharm. Res. 1995, 12, 187-191. 

Independently, simple peptide hydroxamic acids (Z-Gly-L-Leu-NHOH and others) were first observed to inhibit the metalloprotease thermolysin in 1977 9,101 The structure was then further improved to the hydroxamidoalkylmalonyl-peptide moiety by considering the substrate specificity of thermolysin and other metalloproteases 10-121 A summary of hydroxamic acids reported to be inhibitors of various metalloenzymes up to 1983 has been published 131 In 1985 hydroxamido-benzylsuccinyl-L-alanine (kelatorphan) was synthesized and found to be one of the best enkephalinase inhibitors 141... 

Scheme 6 A Synthetic Route to Kelatorphan, an Enkephalinase Inhibitor 14 ...

Bunnett, N.W., et al. 1988. Isolation of endopeptidase-24.11 (EC 3.4.24.11, enkephalinase ) from the pig stomach. Hydrolysis of substance P, gastrin-releasing peptide 10, [Leu5] enkephalin, and [Met5] enkephalin. Gastroenterology 95 952. 

The racemic inhibitor thiorphan 46) 25 inhibits enkephalinase and selectively supports the analgesic effect of enkephalins. 

Endopeptidases cleave internal peptide bonds and include enkephalinase and cathepsin B. Small peptides are relatively resistant to the action of endopeptidases but their activity is significant for large peptides. 

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