title: The novel endomorphin degradation blockers Tyr-Pro-DClPhe-Phe-NH (EMDB-1) and Tyr-Pro-Ala-NH (EMDB-2) prolong endomorphin-2 action in rat ileum in vitro.
abstract: The endogenous opioid system is involved in the control of gastrointestinal (GI) motility. The potential use of endogenous MOR ligands, endomorphins (EMs), as therapeutics is limited because of their rapid enzymatic degradation and short duration of action. Targeting enzymatic degradation is an approach to prolong EM activity. In the present study, we characterized the effects of novel blockers of EM degradation in GI tissue preparation in vitro. The effects of actinonin, diprotin A (DIP) and the novel peptide EM degradation blockers Tyr-Pro-DClPhe-Phe-NH(2) (EMDB-1), Tyr-Pro-Ala-NH(2) (EMDB-2) and Tyr-Pro-Ala-OH (EMDB-3) on EM-2-mediated inhibition of electrically induced cholinergic twitch contractions were compared in rat ileum in vitro using an organ bath. EMDB-1 and EMDB-2 significantly prolonged the inhibitory effect of EM-2 on smooth muscle contractility in rat ileum. EMDB-2 extended the EM-2 action for up to 60 min compared to 10 min in controls and was more potent than the conventional peptidase inhibitor DIP. EMDB-1 and EMDB-2 are potent EM degradation blockers, which prolong the inhibitory effects of EM-2 on smooth muscle contractility in rat ileum. These novel compounds may be of future use when targeting the endogenous opioid system in the treatment of GI motility disorders such as diarrhea.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
authors.forename: Renata
authors.initials: R
authors.lastname: Perlikowska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gach
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: do-Rego
authors.forename: Aurore
authors.initials: A
authors.lastname: Cravezic
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
authors.forename: Martin A
authors.initials: MA
authors.lastname: Storr
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats
chemical_list: D006877:Hydroxamic Acids; D009842:Oligopeptides; C105294:endomorphin 2; C041445:diprotin A; C010531:actinonin