Novel inhibitors of enkephalin-degrading enzymes. III: 4-Carboxymethylamino-4-oxo-3 (phenylamino) butanoic acids as enkephalinase inhibitors.
4-Carboxymethylamino-4-oxo-3-(4'-aminophenylamino) butanoic acid (25), its ethyl ester (26) and the corresponding unsubstituted-aryl analogues (17) and (16) are fairly potent inhibitors of enkephalinase (neutral endopeptidase; EC 3.4.24.11), Ki = 0.14-0.39 microM, with weak inhibitory potency, Ki = 15-75 microM, towards aminopeptidase MII. In the mouse abdominal constriction test, the esters (26) and (16) showed systemic inhibitory (antinociceptive) activity with ED50 values 62 +/- 3.05 and 81 +/- 1.74 mg/kg respectively. In the mouse tail immersion test, both (26) and (16) exhibited antinociceptive activity when administered intracerebroventricularly and (26) also exhibited a systemic effect which was only partially reversed by naltrexone. The antinociceptive effect seen with (26) reflects its ranking in vitro as an inhibitor of enkephalinase (Ki = 0.14 microM) but it is possible that this effect is not totally opioid-mediated. Compounds (26) and (16) represent the first combined inhibitors of enkephalinase and aminopeptidase MII.
Patel
A
A
Welsh School of Pharmacy, U.W.C.C., Cardiff U.K.
Smith
H J
HJ
Sewell
R D
RD
D000005:Abdomen; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002087:Butyrates / Q000138:chemical synthesis / Q000494:pharmacology*; D007202:Indicators and Reagents; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D009271:Naltrexone / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement; D013329:Structure-Activity Relationship
D000700:Analgesics; D002087:Butyrates; D007202:Indicators and Reagents; D009271:Naltrexone; D000626:Aminopeptidases; D015260:Neprilysin