2. Academic Validation
  3. Design, synthesis and preclinical evaluation of muscarine receptor antagonists via a scaffold-hopping approach

Design, synthesis and preclinical evaluation of muscarine receptor antagonists via a scaffold-hopping approach

  • Eur J Med Chem. 2023 Oct 21:262:115891. doi: 10.1016/j.ejmech.2023.115891.
Marlon Millard 1,  Jonas Kilian 2,  Marius Ozenil 3,  Mariella Mogeritsch 1,  Verena Schwingenschlögl-Maisetschläger 2,  Wolfgang Holzer 1,  Marcus Hacker 3,  Thierry Langer 1,  Verena Pichler 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.
  • 2 Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences, University of Vienna, Vienna, Austria.
  • 3 Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.
  • 4 Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria. Electronic address: verena.pichler@univie.ac.at.
PMID: 37897926 DOI: 10.1016/j.ejmech.2023.115891
Abstract

Our research group recently identified a rearrangement product of pirenzepine as starting point for a comprehensive rational drug design approach towards orthosteric Muscarinic Acetylcholine Receptor ligands. Chemical reduction and bioscaffold hop lead to the development of sixteen promising compounds featuring either a benzimidazole or carbamate moiety, all exhibiting comparable pharmacophoric characteristics. The synthesized compounds were characterized by NMR, HR-MS, and RP-HPLC techniques. Subsequent evaluation encompassed binding affinity assessment on CHO-hM1-5 cells, mode of action determination, and analysis of physico-chemical parameters. The CNS MPO score indicated favorable drug-like attributes and potential CNS activity for the antagonistic ligands. The most promising compounds displayed Ki-values within a desirable low nanomolar range, and their structural features allow for potential carbon-11 radiolabeling. Our optimization efforts resulted in compounds with a remarkable 138-fold increase in binding affinity compared to the previously mentioned rearrangement product towards human M5, suggesting their prospective utility in positron emission tomography applications.

Keywords

Muscarinic acetylcholine receptors; Orthosteric binding site; Pirenzepine.

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