Analgesic effect of actinonin, a new potent inhibitor of multiple enkephalin degrading enzymes.
Actinonin, previously isolated as an antibiotic and shown to be an inhibitor of aminopeptidase M (EC 3.4.11.2), has now been shown to inhibit three enkephalin-degrading enzymes from guinea-pig striatum. The values of IC50 were 0.39 microM for striatal membrane aminopeptidase ("enkephalin-aminopeptidase") and 5.6 microM striatal membrane neutral endopeptidase ("enkephalinase A"). Furthermore, soluble dipeptidylaminopeptidase in a rat whole brain homogenate was also inhibited by actinonin with the IC50 value of 1.1 microM. Actinonin administered intracisternally (i.cist., 50 micrograms) or intraperitoneally (i.p., 100 mg/kg), potentiated the analgesic action of met-enkephalin (50 micrograms i.cist.). analgesia by a tail-flick test. The potentiating activity of actinonin i.p. to met-enkephalin analgesia was almost the same potency as that of thiorphan, whereas the inhibitory activity of actinonin against enkephalinase A was 1/1000 that of thiorphan. Actinonin alone, administered either i.cist. or i.p., showed an analgesic action as estimated by the tail-flick test.
Hachisu
M
M
Hiranuma
T
T
Murata
S
S
Aoyagi
T
T
Umezawa
H
H
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000698:Analgesia; D000818:Animals; D003342:Corpus Striatum / Q000201:enzymology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D010450:Endopeptidases; D004744:Enkephalin, Methionine; D006168:Guinea Pigs; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D015260:Neprilysin; D011480:Protease Inhibitors; D015244:Thiorphan; D008625:Tiopronin / Q000031:analogs & derivatives / Q000494:pharmacology
D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D004744:Enkephalin, Methionine; D015244:Thiorphan; D008625:Tiopronin; D010450:Endopeptidases; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D015260:Neprilysin; C010531:actinonin