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 K i of 0.35 nM. Racemates 4 , 6 , and 7 were separated into enantiomers. (+)-(4a R ,5 S ,8a S )-Configured enantiomer 7b was identified as a high affinity ( K i  = 0.25 nM) κ ligand with high selectivity over μ and δ receptors. It acts as full agonist with an EC 50 value of 2.0 nM in the [ 35 S]GTPγS assay, while enantiomer 7a showed an EC 50 value of 1000 nM.