title: Conformationally restricted κ-opioid receptor agonists: Synthesis and pharmacological evaluation of diastereoisomeric and enantiomeric decahydroquinoxalines.
abstract: All diastereoisomeric decahydroquinoxalines representing conformationally restricted analogs of κ agonists U-50,488 and GR-89,696 have been prepared. Cis/trans configured compound 7 is by far the highest binding diastereoisomer with a Ki of 0.35 nM. Racemates 4, 6, and 7 were separated into enantiomers. (+)-(4aR,5S,8aS)-Configured enantiomer 7b was identified as a high affinity (Ki=0.25 nM) κ ligand with high selectivity over μ and δ receptors. It acts as full agonist with an EC50 value of 2.0 nM in the [(35)S]GTPγS assay, while enantiomer 7a showed an EC50 value of 1000 nM.
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: 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: Roy P M
authors.initials: RP
authors.lastname: Storcken
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: Bram
authors.initials: B
authors.lastname: van Oss
authors.affiliation: Mercachem, Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
authors.forename: Richard N S
authors.initials: RN
authors.lastname: van der Haas
authors.affiliation: Organisch-Chemisches Institut der Universität Münster, Corrensstraße 40, D-48149 Münster, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Fröhlich
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, 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. Electronic address: michael.soeberdt@wolff-arzneimittel.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Soeberdt
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013237:Stereoisomerism
chemical_list: D010879:Piperazines; D011759:Pyrrolidines; D011810:Quinoxalines; D017473:Receptors, Opioid, kappa; C071609:GR 89696; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
keywords: Decahydroquinoxalines; Diastereoisomers; Hydrogenation; Relationship between configuration and κ affinity; Resolution of enantiomers; SAR; κ agonists; κ-Opioid receptor