Thiorphan

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. 

Because renal vasodilatation and hyperfiltration are often associated with a natriuretic response, a number of activators or inhibitors of endogenous vasoactive systems can cause increased NaCl excretion, and some of these may be developed into compounds of clinical interest in special situations. Such agents include natriuretic pqDtides most notably B-type natriuretic peptide (nesiritide), neutral endopeptidase (NEP) inhibitors (thiorphan, phosphoramidon), mixed NEP and ACE inhibitors (omapatrilat), guanylin and uroguanylin, kinins, prostaglandins of the E series, adrenomedullin, relaxin, prolactin, and others. 

These zinc-dependent endopeptidases (meprin A [EC 3.4.24.18] and meprin B [EC 3.4.24.63] ) are members of the peptidase family M12A. They catalyze the hydrolysis of peptide bonds in proteins and peptide substrates. Meprin A, a membrane-bound enzyme that has been isolated from mouse and rat kidney and intestinal brush borders as well as salivary ducts, acts preferentially on carboxyl side of hydrophobic amino acyl residues. Meprin A and B are insensitive to inhibition by phosphora-midon and thiorphan. 

This zinc-dependent endopeptidase [EC 3.4.24.11] catalyzes the hydrolysis of peptide bonds and exhibits preferential cleavage at the amino group of hydrophobic residues in proteins and polypeptides. Neprilysin is a membrane-bound glycoprotein that is inhibited by phos-phoramidon and thiorphan. 

Neutral endopeptidase 1,10-Phenanthroline, phosphoramidon, thiorphan [(2-mercaptomethyl-3-phenyl-propionylamino)-acetic acid]... 

Several classes of potent and selective inhibitors of NEP and APN have been rationally designed. The specificity of NEP is essentially ensured by the Si subsite, which interacts preferentially with aromatic or large hydrophobic moieties, whereas the S2 subsite has a poor specificity [13]. These observations were used to design thiorphan [14] and retrothiorphan [15], which were the first described potent synthetic NEP inhibitors. Protection of the thiol and carboxyl groups of thiorphan led to acetorphan, a compound able to cross the blood-brain barrier (BBB) after systemic administration. Various natural APN inhibitors have been isolated, some of them exhibiting relatively good... 

Pharmacological studies with selective agonists have shown that opioid control of intestinal electrolyte transport is predominantly mediated by delta opioid receptors [58], while the gastrointestinal propulsion is under the control of mu receptors [59,60]. The antidiarrheal effects of NEP inhibitors, such as acetorphan, the prodrug of thiorphan, have been compared to those of an opiate agonist, loperamide, in a model of castor oil-induced diarrhea in rats. When administered peripherally, they produced a delayed onset of diarrhea with no reduction in the gastrointestinal transit [61,62], as is commonly observed with loperamide [63],... 

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

Koch, B.L., Edvinsson, A.A., Koskinen, L.O. (1999). Inhalation of substance P and thiorphan acute toxicity and effects on respiration in conscious guinea pigs. J. Appl. Toxicol. 19 19-23. 

Figure 8.3). Thiorphan is less effective than phosphoramidon and enalapril is inactive. Thus, there is an apparent correlation between the ECE studied in the enzyme assay and that in the isolated tissue.

Enkephalinase Zn(II)(His)2(Glu) (hydrolyzes neuropeptides) Analgesics (thiorphan, phos-phoryl-Leu-Phe)... 

Although tachykinins are important in the airway response to certain interventions, there appears to be little or no tachykinin tone in the absence of intervention. In non-asthmatic or stable asthmatic human airways, neither the NEP inhibitor thiorphan (Cheung et /., 1992, 1993) nor the combined Nkl/Nk2 receptor antagonist FK224 (Ichinose et al., 1992) has any effect on baseline specific airways resistance. Likewise, alterations in NEP activity do not contribute to the enhanced bronchoconstrictive responses to NkA observed in patients with mild asthma. Asthmatic patients respond to inhaled thiorphan with an increase in NkA-induced bronchoconstriction similar in magnitude to that documented in non-asthmatic subjects (Cheung et al., 1992, 1993). 

Cheung, D., Bel, E.H., Den Hartigh, J. etal. (1992). The effect of an inhaled neutral endopeptidase inhibitor, thiorphan, on airway responses to neurokinin A in normal humans in vivo. Am. Rev. Respir. Dis. 145, 1275-1280. 

Maggj, C.A., Patacchini, R., Perretti, F. etal. (1990). The effect of thiorphan and epithelium removal on contractions and tachykinin release produced by activation of capsaicin-sensitive aflferents in the guinea-pig isolated bronchus. Naunyn Schmiedeberas Arch. Pharmacol. 341, 74-79. 

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