Thiorphan and analogs: lack of correlation between potency to inhibit ‘enkephalinase A’ in vitro and analgesic potency in vivo : L.G. Mendelsohn, B.G. Johnson, W.L. Scott and R.C.A. Frederickson, J. Pharmacol. exp. Ther., 234 (1985) 386–390

Abstract

The potencies of the R and S isomers of thiorphan and rigid analogs of thiorphan to produce analgesia in a mouse hot-plate assay have been compared with their potencies to inhibit enkephalin degradation by rat brain "enkephalinase A." The R and S isomers of thiorphan were equipotent as enzyme inhibitors (IC50 approximately 10(-9) M) but had significantly different analgesic profiles when injected i.c.v. Rigid analogs of thiorphan were less potent enzyme inhibitors (IC50 values of 10(-7) - 10(-4) M) but produced analgesia and potentiated Tyr-D-Ala-Gly-Phe-Met-NH2 induced analgesia at doses (i.c.v.) comparable to thiorphan. These observations suggest that inhibitors of enkephalinase A produce analgesia through a pharmacological mechanism which is not directly related to inhibition of enkephalin degradation.