title: Synthesis and characterization of potent and selective mu-opioid receptor antagonists, [Dmt(1), D-2-Nal(4)]endomorphin-1 (Antanal-1) and [Dmt(1), D-2-Nal(4)]endomorphin-2 (Antanal-2).
abstract: To synthesize potent antagonists of the mu-opioid receptor, we prepared a series of endomorphin-1 and endomorphin-2 analogues with 3-(1-naphthyl)-d-alanine (d-1-Nal) or 3-(2-naphthyl)-d-alanine (d-2-Nal) in position 4. Some of these analogues displayed weak antagonist properties. We tried to strengthen these properties by introducing the structurally modified tyrosine residue 2,6-dimethyltyrosine (Dmt) in place of Tyr1. Among the synthesized compounds, [Dmt1, d-2-Nal4]endomorphin-1, designated antanal-1, and [Dmt1, d-2-Nal4]endomorphin-2, designated antanal-2, turned out to be highly potent and selective mu-opioid receptor antagonists, as judged on the basis of two functional assays, the receptor binding assay and the hot plate test of analgesia. Interestingly, another analogue of this series, [Dmt1, d-1-Nal4]endomorphin-1, turned out to be a moderately potent mixed mu-agonist/delta-antagonist.
authors.affiliation: Laboratory of Biomolecular Chemistry, Institute of Biomedicinal Chemistry, Medical University, Lodz, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: do-Rego
authors.forename: Nga N
authors.initials: NN
authors.lastname: Chung
authors.forename: Carole
authors.initials: C
authors.lastname: Lemieux
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
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: Anna
authors.initials: A
authors.lastname: Janecka
mesh_terms: D000331:Aequorin; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D049408:Luminescent Agents; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D000700:Analgesics; D049408:Luminescent Agents; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C517646:endomorphin-1, Dmt(1)-2-Nal(4)-; C517647:endomorphin-2, Dmt(1)-2-Nal(4)-; D000331:Aequorin; D002118:Calcium