title: Novel highly potent mu-opioid receptor antagonist based on endomorphin-2 structure.
abstract: The mu-opioid agonists endomorphin-1 (Tyr-Pro-Trp-Phe-NH(2)) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH(2)) exhibit an extremely high selectivity for the mu-opioid receptor and thus represent a potential framework for modification into mu-antagonists. Here we report on the synthesis and biological evaluation of novel [d-2-Nal(4)]endomorphin-2 analogs, [Sar(2),d-2-Nal(4)]endomorphin-2 and [Dmt(1),Sar(2),d-2-Nal(4)]endomorphin-2 (Dmt=2'6'-dimethyltyrosine; Sar=N-methylglycine, sarcosine; d-2-Nal=3-(2-naphthyl)-d-alanine). [Dmt(1),Sar(2),d-2-Nal(4)]endomorphin-2 possessed very high affinity for the mu-opioid receptor (IC(50)=0.01+/-0.001 nM) and turned out to be a potent and extremely selective mu-opioid receptor antagonist, as judged by the in vitro aequorin luminescence-based calcium assay (pA(2)=9.19). However, in the in vivo hot plate test in mice this analog was less potent than our earlier mu-opioid receptor antagonist, [Dmt(1),d-2-Nal(4)]endomorphin-2 (antanal-2). The exceptional mu-opioid receptor in vitro activity and selectivity of [Dmt(1), Sar(2),d-2-Nal(4)]endomorphin-2 makes this analog a valuable pharmacological tool, but further modifications are needed to improve its in vivo profile.
authors.affiliation: Laboratory of Biomolecular Chemistry, Institute of Biomedicinal Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, PL, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: do-Rego
authors.forename: Tomasz
authors.initials: T
authors.lastname: Janecki
authors.forename: Renata
authors.initials: R
authors.lastname: Staniszewska
authors.forename: Jeroen
authors.initials: J
authors.lastname: Poels
authors.forename: Jozef Vanden
authors.initials: JV
authors.lastname: Broeck
authors.forename: Jean
authors.initials: J
authors.lastname: Costentin
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D011487:Protein Conformation; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105294:endomorphin 2; D002118:Calcium