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

Marlon Millard, Jonas Kilian, Marius Ozenil, Mariella Mogeritsch, Verena Schwingenschlögl-Maisetschläger, Wolfgang Holzer, Marcus Hacker, Thierry Langer, Verena Pichler (Corresponding author)

Publications: Contribution to journalArticlePeer Reviewed

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-hM 1-5 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 K i-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 M 5, suggesting their prospective utility in positron emission tomography applications.

Original languageEnglish
Article number115891
JournalEuropean Journal of Medicinal Chemistry
Volume262
DOIs
Publication statusPublished - 15 Dec 2023

Austrian Fields of Science 2012

  • 104015 Organic chemistry

Keywords

  • Muscarinic acetylcholine receptors
  • Orthosteric binding site
  • Pirenzepine

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