New potent muscarinic receptor ligands bearing the 1,4-dioxane nucleus: Investigation on the nature of the substituent in position 2

Gianfabio Giorgioni, Alessandro Bonifazi, Rosanna Matucci, Federica Matteucci, Alessandro Piergentili, Alessia Piergentili, Wilma Quaglia, Silvia Gervasoni, Giulio Vistoli, Serena Vittorio, Fabio Del Bello

Research output: Contribution to journalArticlepeer-review

Abstract

A new series of muscarinic acetylcholine receptor (mAChR) ligands obtained by inserting different substituents in position 2 of the potent 6,6-diphenyl-1,4-dioxane antagonists 4 and 5 was designed and synthesized to investigate the influence of steric bulk on the mAChR affinity. Specifically, the insertion of a 2-methyl group, affording compounds 6 and 9, resulted as the most favorable modification in terms of affinity for all muscarinic subtypes. As supported by computational studies performed on the hM1 receptor, this substituent may contribute to stabilize the ligand within the binding site by favoring the formation of stable interactions between the cationic head of the ligand and the residue D105. The increase of steric bulk, obtained by replacing the methyl group with an ethyl (7 and 10) and especially a phenyl substituent (8 and 11), caused a marked decrease of mAChR affinity, demonstrating the crucial role played by the steric bulk of the 2-substituent in the mAChR interaction. The most intriguing result was obtained with the tertiary amine 9, which, surprisingly, showed two different pKi values for all mAChRs, with preferential subpicomolar affinities for the M1, M3, and M4 subtypes. Interestingly, biphasic curves were also observed with both the eutomer (S)-(–)-9 and the distomer (R)-(+)-9.

Original languageEnglish (US)
Article numbere2400337
JournalArchiv der Pharmazie
Volume357
Issue number10
DOIs
StatePublished - Oct 2024
Externally publishedYes

Keywords

  • 6,6-diphenyl-1,4-dioxane derivatives
  • biphasic curves in binding assays
  • computational studies
  • muscarinic receptor ligands
  • subpicomolar mAChR affinity

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery

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