title: Effect of potent endomorphin degradation blockers on analgesic and antidepressant-like responses in mice.
abstract: The biological effects of endomorphins (EMs) are short-lasting due to their rapid degradation by endogenous enzymes. Competing enzymatic degradation is an approach to prolong EM bioavailability. In the present study, a series of tetra- and tripeptides of similar to EMs structure was synthesized and tested in vitro and in vivo for their ability to inhibit degradation of EMs. The obtained results indicated that, among the series of analogs, the tetrapeptide Tyr-Pro-d-ClPhe-Phe-NH(2) and the tripeptide Tyr-Pro-Ala-NH(2), which did not bind to the μ-opioid receptors, were potent inhibitors of EM catabolism in rat brain homogenate. In vivo, these two peptides significantly prolonged the analgesic and antidepressant-like effects, induced by exogenous EMs, by blocking EM degrading enzymes. These new potent inhibitors may therefore increase the level and the half life of endogenous EMs and could be used in a new therapeutic strategy against pain and mood disorders, based on increasing of EM bioavailability.
authors.affiliation: Institut Fédératif de Recherches Multidisciplinaires sur les Peptides, IFRMP23, University of Rouen, 76821 Mont-Saint-Aignan Cedex, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Cravezic
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gach
authors.forename: Anna
authors.initials: A
authors.lastname: Wyrebska
authors.forename: Renata
authors.initials: R
authors.lastname: Perlikowska
authors.forename: Jean
authors.initials: J
authors.lastname: Costentin
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Bonnet
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: do Rego
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000493:pharmacokinetics; D006930:Hyperalgesia / Q000188:drug therapy*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009842:Oligopeptides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D013550:Swimming / Q000523:psychology; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D000701:Analgesics, Opioid; D000928:Antidepressive Agents; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C060209:deltorphin II, Ala(2)-; C105294:endomorphin 2; D018819:Dipeptidyl Peptidase 4