In vitro characterization of novel peptide inhibitors of endomorphin-degrading enzymes in the rat brain.
Endomorphins, endogenous mu-opioid receptor ligands, have been shown to exert antinociceptive, antidepressant, anxiolytic, and neuromodulatory effects, as well as to influence cardiovascular, respiratory, and gastrointestinal systems. In the present study, we designed and synthesized a series of tetrapeptides and tripeptides (amides and peptide acids) of similar to endomorphins structure, but with low mu-opioid receptor affinity, and tested them as possible inhibitors of endomorphin-degrading enzymes. The obtained results indicate that the tripeptides Tyr-Pro-Ala-NH2 and Tyr-Pro-Ala-OH, which do not bind to the mu-opioid receptors, are potent inhibitors of endomorphin-degrading enzymes in the rat brain. We suggest that the in vivo administration of these novel analogs may enhance physiological effects of endogenous endomorphins by decreasing the rate of their enzymatic cleavage.
Fichna
Jakub
J
Laboratory of Biomolecular Chemistry, Medical University of Lodz, Lodz, Poland.
Janecka
Anna
A
Bailly
Laetitia
L
Marsais
Francis
F
Costentin
Jean
J
do Rego
Jean-Claude
JC
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists*
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; C105294:endomorphin 2