Analgesic effect of actinonin, a new potent inhibitor of multiple enkephalin degrading enzymes

• Published in: Life sciences (1973) Vol. 41; no. 2; p. 235
• Main Authors: Hachisu, M, Hiranuma, T, Murata, S, Aoyagi, T, Umezawa, H
• Format: Journal Article
• Language: English
• Published: Netherlands 13.07.1987
• Subjects: Aminopeptidases - antagonists & inhibitors; Analgesia; Animals; Corpus Striatum - enzymology; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - antagonists & inhibitors; Drug Synergism; Endopeptidases; Enkephalin, Methionine; Guinea Pigs; Hydroxamic Acids - pharmacology; Male; Neprilysin; Protease Inhibitors; Thiorphan; Tiopronin - analogs & derivatives; Tiopronin - pharmacology
• ISSN: 0024-3205
• DOI: 10.1016/0024-3205(87)90498-X

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.