Thiorphan and analogs: lack of correlation between potency to inhibit "enkephalinase A" in vitro and analgesic potency in vivo.
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.
D000603:Amino Acids, Sulfur / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004745:Enkephalins / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D015260:Neprilysin; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D015244:Thiorphan; D008625:Tiopronin / Q000031:analogs & derivatives / Q000494:pharmacology*
D000603:Amino Acids, Sulfur; D000700:Analgesics; D004745:Enkephalins; D011480:Protease Inhibitors; D015244:Thiorphan; D008625:Tiopronin; D015260:Neprilysin