Synthesis, Biological Evaluation, and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs

Jonas Kilian, Marlon Millard, Marius Ozenil, Dominik Krause, Khadija Ghaderi, Wolfgang Holzer, Ernst Urban, Helmut Spreitzer, Wolfgang Wadsak, Marcus Hacker, Thierry Langer, Verena Pichler

Publications: Contribution to journalArticlePeer Reviewed

Abstract

The muscarinic acetylcholine receptor family is a highly sought-after target in drug and molecular imaging discovery efforts aimed at neurological disorders. Hampered by the structural similarity of the five subtypes' orthosteric binding pockets, these efforts largely failed to deliver subtype-selective ligands. Building on our recent successes with arecaidine-derived ligands targeting M 1, herein we report the synthesis of a related series of 11 hydroxylated arecaidine esters. Their physicochemical property profiles, expressed in terms of their computationally calculated CNS MPO scores and HPLC-logD values, point towards blood-brain barrier permeability. By means of a competitive radioligand binding assay, the binding affinity values towards each of the individual human mAChR subtypes hM 1- hM 5 were determined. The most promising compound of this series 17b was shown to have a binding constant towards hM 1 in the single-digit nanomolar region (5.5 nM). Similar to our previously reported arecaidine-derived esters, the entire series was shown to act as hM1R antagonists in a calcium flux assay. Overall, this study greatly expanded our understanding of this recurring scaffolds' structure-activity relationship and will guide the development towards highly selective mAChRs ligands.

Original languageEnglish
Article number3173
Number of pages21
JournalMolecules
Volume27
Issue number10
DOIs
Publication statusPublished - May 2022

Austrian Fields of Science 2012

  • 104015 Organic chemistry

Keywords

  • Arecoline/analogs & derivatives
  • Binding, Competitive
  • Humans
  • Ligands
  • Receptors, Muscarinic/metabolism
  • Signal Transduction
  • SYSTEM
  • HYDROGENATION
  • M1
  • muscarinic acetylcholine receptors
  • drug development
  • molecular docking
  • LIGANDS
  • OPTIMIZATION
  • RECEPTORS
  • EFFICIENT
  • BINDING

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