The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice

Abstract

There is both theoretical and therapeutic interest in establishing whether the signals conveyed by the enkephalins are turned off under the action of a specific peptidase which might, in this case, represent a target for a new class of psychoactive agents. Enkephalinase, a dipeptidyl carboxypeptidase cleaving the Gly3-Phe4 bond of enkephalins and distinct fropm angiotensin coverting enzyme (ACE), might be selectively involved in enkephalinergic transmission. It is a membrane-bound enzyme whose localization in the vicinity of opiate receptors in the central nervous system is suggested by parallel regional and subcellular distributions as well as by the effects of lesions. Such a role is further supported by the ontogenetic development of enkephalinase, its substrate specificity accounting for the increased biological activity of several enkephalin analogues and its adaptive increase following chronic treatment with morphine. To investigate the functional role of this enzyme further, we have designed a potent and specific enkephalinase inhibitor. We report here that this compound, thiorphan [(DL-3-mercapto-2-benzylpropanoyl)-glycine; patent no. 8008601] protects the enkephalins from the action of enkephalinase in vitro in nanomolar concentration and in vivo after either intracerebroventricular or systemic administration. In addition, thiorphan itself displays antinociceptive activity which is blocked by naloxone, an antagonist of opiate receptors.

5-HT-Induced, 5-HT3 Receptor-Mediated, and Ruthenium Red-and Capsaicin-Sensitive Positive Chronotropic Effects in the Isolated Guinea Pig Atrium

“…These observations suggested that 5-HT-induced tachycardia is selectively sensitive to capsaicin treatment and that the effect might be mediated through release of cardiotonic peptide(s). Furthermore, we found that 5-HT-induced tachycardia was potentiated by thiorphan, an inhibitor of peptide degeneration (16). This result further supported the suggestion that the effect of 5-HT might be mediated through release of bioactive peptide(s).…”

The Role of Bestatin-Sensitive Aminopeptidase, Angiotensin Converting Enzyme and Thiorphan-Sensitive "Enkephalinase" in the Potency of Enkephalins in the Guinea-Pig Ileum

“…However, Cohen et al (2) showed that the inhibitory potency of enkephalin in guinea-pig ileum was not enhanced by puromycin, but augmented by bestatin, an aminopeptidase inhibitor of bacterial origin (7); and the degradation of 3H-enkephalin after incubation with guinea-pig ileum was not altered with puromycin, but decreased with bestatin. On the other hand, it was reported (3) that the inhibitory potency of enkephalin in guinea-pig ileum was not altered with either thiorphan, an inhibitor of "enkephalinase" (8) , or captopril, an angio tensin converting enzyme inhibitor (9). However, Kosterlitz and his colleague (4,5) showed that the greatest increase in potency of enkephalin in guinea-pig ileum was obtained with the combination of bestatin, captopril, thiorphan and L-leucyl-L-leucine.…”

Enkephalin degrading enzymes are present in the electric organ of Torpedo californica

“…Puromycin (100 /IM) and bestatin (10 PM) inhibited almost completely the activity of the electric organ aminopeptidase (90 and 86% inhibition respectively) and had no activity (bestatin) or low inhibitory activity (puromycin) toward the soluble endopeptidase. Thiorphan (10 pM), a potent inhibitor of the brain endopeptidase enkephalinase [21], did not affect the aminopeptidase activity but completely inhibited the soluble endopeptidase (94% inhibition). Similar results were obtained with the membrane associated endopeptidase.…”