Enantiomers of 2-[(Acylamino)ethyl]-1,4-benzodiazepines, Potent Ligands of k-Opioid Receptor. Chiral Chromatographic Resolution, Configurational Assignment and Biological Activity

Compounds 2a and 3a-e are racemic 2-[(acylamino)ethyl]-1,4-benzodiazepines, tifluadom analogs, with high affinity and selectivity towards the κ-opioid receptor. We describe the enantiomeric separation of all compounds through liquid chromatography with chiral stationary phases, as well as the resolution of the enantiomers of the most interesting compounds, 2a and 3a, by the semipreparative column Chiralpak AD. The configuration of the resolved enantiomers was investigated: The comparative study of CD and 1H NMR spectra shows that compounds (-)-2a and (-)-3a have the same absolute configuration of (+)-(S)-tifluadom. A study on the stereoselective interaction with opiate receptors is reported. © 2001 Wiley-Liss, Inc.