Thiorphan and analogs: lack of correlation between potency to inhibit "enkephalinase A" in vitro and analgesic potency in vivo
Mendelsohn, L.G.; Johnson, B.G.; Scott, W.L.; Frederickson, R.C.
Journal of Pharmacology and Experimental Therapeutics 234(2): 386-390
1985
ISSN/ISBN: 0022-3565 PMID: 3894620 Document Number: 255710
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.