Aminopeptidase inhibitory properties and analgesic activity of (2S,3R)-3,7-diamino-2-hydroxy-heptanoic acid containing tripeptide analogues of the N-terminal tripeptide of probestin.
(2S,3R)-3,7-Diamino-2-hydroxy-heptanoyl-Leu-Pro-OH [(2S,3R)-DAHHA-Leu-Pro-OH, 4], analogue of the N-terminal tripeptide of probestin, has been synthesized, and tested as inhibitor of AP-B, Leu-AP, AP-M, and enkephalin-degrading APs, and as analgesic. In order to establish structure-activity relationships the dipeptide (2S,3R)-DAHHA-Pro-OH (5) and the tripeptide (2S,3R)-DAHHA-Ala-Pro-OH (6) were also prepared. Compounds 4 and 6 were potent and selective inhibitors of enkephalin-degrading APs and showed a prolonged antinociceptive effect.
Herranz
R
R
Instituto de Química Médica, C.S.I.C., Madrid, Spain.
Vinuesa
S
S
Pérez
C
C
García-López
M T
MT
De Ceballos
M L
ML
Murillo
F M
FM
del Río
J
J
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D006538:Heptanoic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*
D000700:Analgesics; D006538:Heptanoic Acids; D009842:Oligopeptides; C063432:probestin; C077161:3,7-diamino-2-hydroxyheptanoyl-leucyl-proline; C077162:3,7-diamino-2-hydroxyheptanoyl-alanyl-proline; D000626:Aminopeptidases