The replacement of the 2-methoxy substituent of N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine improves the selectivity for 5-HT1Areceptor over α1-adrenoceptor and D2-like receptor subtypes

Fabio Del Bello, Alessandro Bonifazi, Mario Giannella, Gianfabio Giorgioni, Alessandro Piergentili, Riccardo Petrelli, Carlo Cifani, Maria Vittoria Micioni Di Bonaventura, Thomas M. Keck, Angelica Mazzolari, Giulio Vistoli, Antonio Cilia, Elena Poggesi, Rosanna Matucci, Wilma Quaglia

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine (3) is a potent 5-HT1Areceptor and α1d-adrenoceptor (α1d-AR) ligand. Analogues 5–10 were rationally designed and prepared to evaluate whether electronic and/or lipophilic properties of substituents in the ortho position of its phenoxy moiety exert any favorable effects on the affinity/activity at 5-HT1Areceptor and improve selectivity over α1-ARs. To rationalize the experimental observations and derive information about receptor-ligand interactions of the reported ligands, docking studies, using 5-HT1Aand α1d-AR models generated by homology techniques, and a retrospective computational study were performed. The results highlighted that proper substituents in position 2 of the phenoxy moiety of 3 selectively address the ligands toward 5-HT1Areceptor with respect to α1-ARs and D2-like receptor subtypes. Methoxymethylenoxy derivative 9 showed the best 5-HT1Aselectivity profile and the highest potency at 5-HT1Areceptor, behaving as a partial agonist. Finally, 9, tested in light/dark exploration test in mice, significantly reduced anxiety-linked behaviors. Therefore, it may be considered a lead for the design of partial agonists potentially useful in the treatment of disorders in which 5-HT1Areceptor is involved.

Original languageEnglish (US)
Pages (from-to)233-244
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume125
DOIs
StatePublished - 2017

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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