title: In vitro opioid activity profiles of 6-amino acid substituted derivatives of 14-O-methyloxymorphone.
abstract: A series of 6-amino acid conjugates (glycine, alanine and phenylalanine) of the highly potent opioid analgesic 14-O-methyloxymorphone was developed in an effort to obtain agonists that would have potentially limited ability to cross the blood-brain barrier. Binding studies revealed that all derivatives displayed high affinities (0.77-2.58 nM) at the mu-opioid receptor in rat brain membranes. They were potent agonists in mouse vas deferens preparation (IC(50)=5.52-26.8 nM). While the alpha-amino acid epimers are favoured by mu-opioid receptors, the beta-epimers proved to have increased interaction with delta-sites. Only the beta-phenylalanine conjugate showed some preference for delta- over mu-opioid receptors and delta-opioid receptor agonist activity. The relatively high delta-opioid receptor affinity of this analogue was also predicted by molecular modelling studies. The newly developed ionizable derivatives could find clinical applications as potent analgesics without the adverse actions of centrally acting opioids.
authors.affiliation: Division of Pharmaceutical Chemistry, Department of Pharmacy, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria. Marianna.Spetea@uibk.ac.at
authors.forename: Mariana
authors.initials: M
authors.lastname: Spetea
authors.forename: Tamas
authors.initials: T
authors.lastname: Friedmann
authors.forename: Pal
authors.initials: P
authors.lastname: Riba
authors.forename: Johannes
authors.initials: J
authors.lastname: Schütz
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wunder
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidhammer
authors.forename: Susanna
authors.initials: S
authors.lastname: Fürst
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009292:Narcotic Antagonists / Q000378:metabolism / Q000494:pharmacology; D010111:Oxymorphone / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D010111:Oxymorphone