Synthesis and inhibitory activities against enkephalin degrading aminopeptidase of H-Trp(Nps)-Lys-OMe analogues bearing chelating groups.
With the aim of increasing the inhibitory potency of the analgesic dipeptide H-Trp(Nps)-Lys-OMe against enkephalin-degrading aminopeptidases, the following derivatives bearing chelating groups at the N-terminus have been synthesized: Ac-Trp(Nps)-Lys-OMe (3), HS(CH2)nCO-Trp(Nps)-Lys-OMe [n = 1 (4), n = 2 (5)], MeOCO(CH2)n-Trp(Nps)-Lys-OMe [n = 1 (6), n = 2 (7)] and analogues in which the N alpha-amino group has been replaced by a methoxycarbonyl group (8) and a bidentate hydroxamate function (9), respectively. The inhibitory activities of all these compounds and the S-protected derivatives EtNHCOS(CH2)nCO-Trp(Nps)-Lys-OMe [n = 1 (16), n = (17)] against the mentioned enzyme, isolated from rat striatum, are compared with those of the parent dipeptide 2 and bestatin. All the new derivatives showed, in general, inhibitory potencies of the same order of magnitude as compound 2.
González-Muñiz
R
R
Instituto de Química Médica, Madrid, Spain.
Harto
J R
JR
de Ceballos
M L
ML
del Río
J
J
García-López
M T
MT
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002614:Chelating Agents / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D004745:Enkephalins / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D051381:Rats
D002614:Chelating Agents; D004151:Dipeptides; D004745:Enkephalins; D000626:Aminopeptidases