Enkephalinase is a metallopeptidase that is able to cleave not only neuropeptides and hormones but also immune mediators. Enkephalinase is partially responsible for the inactivation of endogenous enkephalins. Thiorphan, a synthetic enkephalinase inhibitor produces naloxone-reversible analgesia. This generated a great deal of interest. Because it held out the possibility of an entirely new kind of “opioid” analgesic. SCH 32615 competitively antagonizes enkephalinase in vitro and produces analgesia in vivo. An increase in cerebrospinal enkephalin peptides occurs in pregnant women near term. In circumstances wherein endogenous enkephalins are increased, inhibition of their breakdown (enkephalinase inhibition) should enhance their activity and lead to measurable analgesia. Further, since enkephalinase inhibition may produce analgesia with fewer side effects (gastrointestinal and respiratory). Thus, the use of enkephalin inhibitors might lead to analgesia with fewer side effects than more traditional opioids.

SCH 32615 blocks the degradation of Met5-enkephalin by isolated enkephalinase, with a K_i of 19.5 nM. Moreover, SCH 32615, an enkephalinase inhibitor, enhances pregnancy-induced analgesia in mice. At analgesically active doses (1-100 mg/kg s.c., 60 min before killing), SCH 32615 induces a dose-dependent increase in dopamine metabolism in the nucleus accumbens but is ineffective in the striatum and in the prefrontal cortex. In addition, the study has supported the hypothesis that inhibition of the in vivo degradation of enkephalins induced by the systemic administration of SCH 32615 increases the enkephalinergic tone in the central nervous system and thereby activates the mesolimbic dopaminergic neurons.

In summary, SCH 32615 is an enkephalinase inhibitor. It can enhance surgery- and pregnancy-induced analgesia in mice. It also increases dopamine metabolism in the nucleus accumbens of the rat.

Reference:

Jayaram A, et al. Anesth Analg. 1995;80(5):944-948. ; Giorgi O, et al. Eur J Pharmacol. 1991;196(2):137-142.