Novel inhibitors of enkephalin-degrading enzymes. I: Inhibitors of enkephalinase by penicillins.
Several penicillins have been found to have pro-antinociceptive properties and also to be enkephalinase (neutral endopeptidase-24.11) inhibitors, carfecillin being the most potent. Carfecillin i.c.v. (but not i.p.) had significant antinociceptive activity in the mouse tail immersion test and completely suppressed abdominal constrictions (acetic acid) in mice (IC50 = 23 micrograms/animal). In combination with (D-Ala2-D-leu5)-enkephalin (DADL) i.c.v. in the abdominal constriction test the complete protection observed was reversed by the opioid receptor antagonist naltrexone. Carfecillin was a competitive inhibitor of enkephalinase from mouse brain striata (IC50 = 207 + 57 nM, cf thiorphan 10.6 +/- 1.9 nM) but did not inhibit other known enkephalin- degrading enzymes. Carfecillin provides a new lead structure for the development of more potent enkephalinase inhibitors.
Williams
P S
PS
Welsh School of Pharmacy, University of Wales College of Cardiff, U.K.
Sewell
R D
RD
Smith
H J
HJ
Gonzalez
J P
JP
D000700:Analgesics; D000818:Animals; D001921:Brain / Q000201:enzymology; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009271:Naltrexone / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010146:Pain / Q000503:physiopathology*; D010406:Penicillins / Q000494:pharmacology*; D015244:Thiorphan / Q000494:pharmacology; D013997:Time Factors
D000700:Analgesics; D007527:Isoenzymes; D010406:Penicillins; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; D015244:Thiorphan; D015260:Neprilysin