Ifenprodil Stereoisomers: Synthesis, Absolute Configuration, and Correlation with Biological Activity

Ifenprodil
(1) is a potent GluN2B-selective N-methyl-d-aspartate (NMDA) receptor antagonist
that is used as a cerebral vasodilator and has been examined in clinical
trials for the treatment of drug addiction, idiopathic pulmonary fibrosis,
and COVID-19. To correlate biological data with configuration, all
four ifenprodil stereoisomers were prepared by diastereoselective
reduction and subsequent separation of enantiomers by chiral HPLC.
The absolute configuration of ifenprodil stereoisomers was determined
by X-ray crystal structure analysis of (1R,2S)-1a and (1S,2S)-1d. GluN2B affinity, ion channel inhibitory activity,
and selectivity over α, σ, and 5-HT receptors were evaluated.
(1R,2R)-Ifenprodil ((1R,2R)-1c) showed the highest affinity
toward GluN2B-NMDA receptors (Ki = 5.8
nM) and high inhibition of ion flux in two-electrode voltage clamp
experiments (IC50 = 223 nM). Whereas the configuration
did not influence considerably the GluN2B-NMDA receptor binding, (1R)-configuration is crucial for elevated inhibitory activity.
(1R,2R)-Configured ifenprodil (1R,2R)-1c exhibited high selectivity
for GluN2B-NMDA receptors over adrenergic, serotonergic, and σ1 receptors.