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

Peter Molenveld; Renaud Bouzanne des Mazery; Geert Jan Sterk; Roy P M Storcken; Reshma Autar; Bram van Oss; Richard N S van der Haas; Roland Fröhlich; Dirk Schepmann; Bernhard Wünsch; Michael Soeberdt

doi:10.1016/j.bmcl.2015.09.040

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. Epub 2015 Sep 16.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / chemistry*
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
Crystallography, X-Ray
Inhibitory Concentration 50
Magnetic Resonance Spectroscopy
Molecular Structure
Piperazines / chemistry*
Piperazines / pharmacology
Protein Binding / drug effects
Pyrrolidines / chemistry*
Pyrrolidines / pharmacology
Quinoxalines / chemical synthesis*
Quinoxalines / chemistry
Quinoxalines / pharmacology*
Receptors, Opioid, kappa / agonists*
Stereoisomerism

Substances

Piperazines
Pyrrolidines
Quinoxalines
Receptors, Opioid, kappa
GR 89696
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer