Conformationally restricted κ-opioid receptor agonists: Synthesis and pharmacological evaluation of diastereoisomeric and enantiomeric decahydroquinoxalines

  • Bioorg Med Chem Lett. 2015 Nov 15;25(22):5326-30. doi: 10.1016/j.bmcl.2015.09.040.
Peter Molenveld  1 ,  Renaud Bouzanne des Mazery  1 ,  Geert Jan Sterk  1 ,  Roy P M Storcken  1 ,  Reshma Autar  1 ,  Bram van Oss  1 ,  Richard N S van der Haas  1 ,  Roland Fröhlich  2 ,  Dirk Schepmann  3 ,  Bernhard Wünsch  3 ,  Michael Soeberdt  4
Affiliations
  • 1. Mercachem, Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
  • 2. Organisch-Chemisches Institut der Universität Münster, Corrensstraße 40, D-48149 Münster, Germany.
  • 3. Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
  • 4. Dr. August Wolff GmbH & Co. KG Arzneimittel, Sudbrackstraße 56, D-33611 Bielefeld, Germany. Electronic address: [email protected].
PMID: 26411794 DOI: 10.1016/j.bmcl.2015.09.040
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.

Keywords
Decahydroquinoxalines; Diastereoisomers; Hydrogenation; Relationship between configuration and κ affinity; Resolution of enantiomers; SAR; κ agonists; κ-Opioid receptor.