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.

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