Novel inhibitors of enkephalin-degrading enzymes. II: N5'-substituted-4-thioxohydantoic acids as aminopeptidase inhibitors.
Some 2-substituted-(2'-aminophenyl)-4-thioxohydantoic acids (o-amino PTC-amino acids) have antinociceptive activity when administered (icv) alone (IC50 = 0.04-0.87 microM/animal) and show a striking prolongation of the antinociceptive action of (D-Ala-2 D-Leu5)-enkephalin (DADL) in combination. The effects are thought to be mediated via opioid receptors since they are naloxone-reversible. Although inhibitors of the enkephalin degrading puromycin-insensitive, bestatin-sensitive aminopeptidase (possibly aminopeptidase M) their action is weak (IC50 = 32 microM leucine, 536 microM, glycine) and they might be considered to have a direct antinociceptive effect on opioid receptors. The titled compounds constitute novel 'lead' compounds for the development of potent aminopeptidase M inhibitors.
Yu
Z
Z
Welsh School of Pharmacy, University of Wales College of Cardiff, UK.
Williams
P S
PS
Smith
H J
HJ
Sewell
R D
RD
Patel
A
A
Gonzalez
J P
JP
D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D000700:Analgesics; D000818:Animals; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007202:Indicators and Reagents; D007930:Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010146:Pain / Q000503:physiopathology*; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D013867:Thiohydantoins / Q000138:chemical synthesis* / Q000494:pharmacology; D015244:Thiorphan / Q000494:pharmacology
D000700:Analgesics; D007202:Indicators and Reagents; D011480:Protease Inhibitors; D013867:Thiohydantoins; C067305:N(5)-(2'-aminophenyl)-4-thioxohydantoic acid; C067306:2-(2'-methylpropyl)-N(5)-(2'-aminophenyl)-4-thiohydantoic acid; C067304:N-(N'-(2'-nitrophenyl)thiocarbamyl)pyrrolidine-2-carboxylic acid; D009270:Naloxone; D011392:Proline; D015244:Thiorphan; D000626:Aminopeptidases; D015260:Neprilysin; D007930:Leucine; D005998:Glycine