New Synthesis and Pharmacological Evaluation of Enantiomerically Pure (R)- and (S)-Methadone Metabolites as N-Methyl-d-aspartate Receptor Antagonists

N-Methyl-d-aspartate receptor (NMDAR) is gaining increasing interest as a pharmacological target for the development of fast-acting antidepressants. (S)-Methadone (esmethadone), has recently shown promising efficacy for the treatment of major depressive disorder. However, methods for its enantiopure preparation still rely on complex and expensive resolution procedures. In addition, enantiopure methadone metabolites have never been evaluated for their NMDAR activity. Here, we report the development of a novel chiral pool approach, based on cyclic sulfamidate ring-opening reaction, for the asymmetric synthesis of (R)- and (S)-methadone, and the application of this methodology to the stereodivergent synthesis of 20 enantiopure methadone metabolites. The compounds were evaluated for their NMDAR antagonism and for their affinity toward a series of relevant CNS receptors. Strikingly, N-demethylated (6R)-methadol metabolites retain the higher NMDAR uncompetitive antagonism of (R)-methadone, while presenting lower opioid receptor affinity compared to (S)-methadone. These compounds could represent novel candidates for drug development in CNS disorders.