The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice

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 Gly 3 -Phe 4 bond of enkephalins 1,2 and distinct from angiotensin converting enzyme (ACE) 3–6 , might be selectively involved in enke-phalinergic transmission. It is a membrane-bound enzyme 1,7,8 whose localization in the vicinity of opiate receptors in the central nervous system is suggested by parallel regional 1,7,9 and subcellular 10 distributions as well as by the effects of lesions 9 . Such a role is further supported by the ontogenetic development of enkephalinase 11,12 , its substrate specificity accounting for the increased biological activity of several enkephalin analogues 13 and its adaptive increase following chronic treatment with morphine 1,14 . 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.