title: Design and Synthesis of Enantiomerically Pure Decahydroquinoxalines as Potent and Selective κ-Opioid Receptor Agonists with Anti-Inflammatory Activity in Vivo.
abstract: In order to develop novel κ agonists restricted to the periphery, a diastereo- and enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5-8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5-8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full κ agonistic activity in the [35S]GTPγS assay, and high selectivity over μ, δ, σ1, and σ2receptors as well as the PCP binding site of the NMDA receptor. Several analogues were selective for the periphery. The anti-inflammatory activity of 5-8 after topical application was investigated in two mouse models of dermatitis. The methanesulfonamide 8a containing the (S)-configured hydroxypyrrolidine ring was identified as a potent (Ki= 0.63 nM) and highly selective κ agonist (EC50= 1.8 nM) selective for the periphery with dose-dependent anti-inflammatory activity in acute and chronic skin inflammation.
authors.affiliation: Dr. August Wolff GmbH & Co. KG Arzneimittel , Sudbrackstraße 56, D-33611 Bielefeld, Germany.
authors.forename: Michael
authors.identifier: 0000-0003-2594-9901
authors.initials: M
authors.lastname: Soeberdt
authors.affiliation: Mercachem , Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Molenveld
authors.affiliation: Mercachem , Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
authors.forename: Roy P M
authors.initials: RP
authors.lastname: Storcken
authors.affiliation: Mercachem , Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
authors.forename: Renaud
authors.initials: R
authors.lastname: Bouzanne des Mazery
authors.affiliation: Mercachem , Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Sterk
authors.affiliation: Mercachem , Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
authors.forename: Reshma
authors.initials: R
authors.lastname: Autar
authors.affiliation: Mercachem , Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
authors.forename: Marjon G
authors.initials: MG
authors.lastname: Bolster
authors.affiliation: Mercachem , Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
authors.forename: Clemens
authors.initials: C
authors.lastname: Wagner
authors.affiliation: Mercachem , Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
authors.forename: Sebastianus N H
authors.initials: SN
authors.lastname: Aerts
authors.affiliation: Mercachem , Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
authors.forename: Frank R
authors.initials: FR
authors.lastname: van Holst
authors.affiliation: Mercachem , Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
authors.forename: Anita
authors.initials: A
authors.lastname: Wegert
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster , Correnstraße 48, D-48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Universität Münster , D-48149 Münster, Germany.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tangherlini
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster , Correnstraße 48, D-48149 Münster, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Frehland
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster , Correnstraße 48, D-48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Universität Münster , D-48149 Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: Klinik für Hautkrankheiten, Universitätsklinikium Münster , Von-Esmarch-Straße 58, D-48149 Münster, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Metze
authors.affiliation: Klinik für Hautkrankheiten, Universitätsklinikium Münster , Von-Esmarch-Straße 58, D-48149 Münster, Germany.|Kompetenzzentrum chronischer Pruritus (KCP), Universitätsklinikium Münster , Von-Esmarch-Straße 58, D-48149 Münster, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Lotts
authors.affiliation: Dr. August Wolff GmbH & Co. KG Arzneimittel , Sudbrackstraße 56, D-33611 Bielefeld, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Knie
authors.affiliation: Eurofins Panlabs Taiwan, Ltd. , 158 Li-Teh Road, Peitou, Taipei 11259, Taiwan.
authors.forename: Kun-Yuan
authors.initials: KY
authors.lastname: Lin
authors.affiliation: Eurofins Panlabs Taiwan, Ltd. , 158 Li-Teh Road, Peitou, Taipei 11259, Taiwan.
authors.forename: Tai-Yu
authors.initials: TY
authors.lastname: Huang
authors.affiliation: Eurofins Panlabs Taiwan, Ltd. , 158 Li-Teh Road, Peitou, Taipei 11259, Taiwan.
authors.forename: Chih-Ching
authors.initials: CC
authors.lastname: Lai
authors.affiliation: Klinik für Hautkrankheiten, Universitätsklinikium Münster , Von-Esmarch-Straße 58, D-48149 Münster, Germany.|Kompetenzzentrum chronischer Pruritus (KCP), Universitätsklinikium Münster , Von-Esmarch-Straße 58, D-48149 Münster, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Ständer
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster , Correnstraße 48, D-48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Universität Münster , D-48149 Münster, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
authors.affiliation: Dr. August Wolff GmbH & Co. KG Arzneimittel , Sudbrackstraße 56, D-33611 Bielefeld, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Abels
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D003872:Dermatitis / Q000188:drug therapy* / Q000473:pathology; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D011810:Quinoxalines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D012867:Skin / Q000187:drug effects* / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D011810:Quinoxalines; D017473:Receptors, Opioid, kappa