| Literature DB >> 26411794 |
Peter Molenveld1, Renaud Bouzanne des Mazery1, Geert Jan Sterk1, Roy P M Storcken1, Reshma Autar1, Bram van Oss1, Richard N S van der Haas1, Roland Fröhlich2, Dirk Schepmann3, Bernhard Wünsch3, Michael Soeberdt4.
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.Entities:
Keywords: Decahydroquinoxalines; Diastereoisomers; Hydrogenation; Relationship between configuration and κ affinity; Resolution of enantiomers; SAR; κ agonists; κ-Opioid receptor
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Year: 2015 PMID： 26411794 DOI： 10.1016/j.bmcl.2015.09.040
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823