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

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

  • J Med Chem. 2025 Mar 13;68(5):5455-5470. doi: 10.1021/acs.jmedchem.4c02605.
Marco Banzato 1,  Alberto Furlan 1 2,  Patrizia Locatelli 2,  Jacopo Sgrignani 2,  Alberto Ongaro 1,  Alessandro Dolmella 1,  Sara De Martin 1,  Stefano Comai 1 3 4 5,  Andrea Cavalli 2,  Charles Inturrisi 6,  Ezio Bettini 7,  Paolo L Manfredi 6,  Andrea Mattarei 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Francesco Marzolo 5, 35131 Padua, Italy.
  • 2 Institute for Research in Biomedicine, Via Chiesa 5, 6500 Bellinzona, Switzerland.
  • 3 Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, 35131 Padua, Italy.
  • 4 Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada.
  • 5 IRCSS San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy.
  • 6 Relmada Therapeutics, Coral Gables, Florida 33134, United States.
  • 7 In Vitro Pharmacology Department, Aptuit, An Evotec Company, Via Alessandro Fleming, 4, 37135 Verona, Italy.
PMID: 39999356 DOI: 10.1021/acs.jmedchem.4c02605
Abstract

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.

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