Analgesic dipeptide derivatives. 7. 3,7-Diamino-2-hydroxyheptanoic acid (DAHHA) containing dipeptide analogues of the analgesic compound H-Lys-Trp(Nps)-OMe.
A series of diastereomeric dipeptides, analogues of the analgesic compound H-Lys-Trp(Nps)-OMe (2), containing 3,7-diamino-2-hydroxyheptanoic acid (DAHHA) and 2-[(o-nitrophenyl)sulfenyl]tryptophan [Trp(Nps)] has been synthesized. These compounds were tested as enkephalin-degrading aminopeptidases (APs), AP-M and AP-B inhibitors, and analgesics. The inhibitory potencies and the antinociceptive effects depended on the stereochemistry of the compounds. (2S,3R)-DAHHA-L-Trp(Nps)-OMe (26d) was a highly potent and selective enkephalin-degrading APs inhibitor, with an IC50 value in the 10(-8) M range. Although this derivative was about 10(3)-fold more potent than 2 against these enzymes, their antinociceptive effects were completely similar. These results indicate that the inhibitory capacity of this series of Trp(Nps)-containing dipeptides against enkephalin-degrading enzymes is not an important factor for their antinociceptive effects.
Herranz
R
R
Instituto de Química Médica, C.S.I.C., Madrid, Spain.
Vinuesa
S
S
Pérez
C
C
García-López
M T
MT
López
E
E
de Ceballos
M L
ML
Del Río
J
J
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000698:Analgesia; D000700:Analgesics / Q000138:chemical synthesis*; D000818:Animals; D001921:Brain / Q000201:enzymology; D018826:CD13 Antigens; D002462:Cell Membrane / Q000201:enzymology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D004745:Enkephalins / Q000378:metabolism; D006538:Heptanoic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D004151:Dipeptides; D004745:Enkephalins; D006538:Heptanoic Acids; C060370:H-lysyl-2-(2-nitrophenylsulfenyl)tryptophan methyl ester; C073521:3,7-diamino-2-hydroxyheptanoic acid-2-(2-nitrophenylsulfenyl)tryptophan methyl ester; D000626:Aminopeptidases; D018826:CD13 Antigens; C019721:aminopeptidase B