1,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity

Silvia Franchini, Claudia Sorbi, Pasquale Linciano, Gianluca Carnevale, Annalisa Tait, Simone Ronsisvalle, Michela Buccioni, Fabio Del Bello, Antonio Cilia, Lorenza Pirona, Nunzio Denora, Rosa Maria Iacobazzi, Livio Brasili

Research output: Contribution to journalArticlepeer-review

Abstract

A series of compounds generated by ring expansion/opening and molecular elongation/simplification of the 1,3-dioxolane scaffold were prepared and tested for binding affinity at 5-HT1AR and α1 adrenoceptors. The compounds with greater affinity were selected for further functional studies. N-((2,2-diphenyl-1,3-dioxan-5-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-ammonium hydrogen oxalate (12) emerged as highly potent full agonist at the 5-HT1AR (pKi 5-HT1A = 8.8; pD2 = 9.22, %Emax = 92). The pharmacokinetic data in rats showed that the orally administered 12 has a high biodistribution in the brain compartment. Thus, 12 was further investigated in-vivo, showing an anxiolytic and antidepressant effect. Moreover, in the formalin test, 12 was able to decrease the late response to the noxious stimulus, indicating a potential use in the treatment of chronic pain.

Original languageEnglish
Pages (from-to)310-325
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume176
DOIs
Publication statusPublished - Aug 15 2019

Keywords

  • 1,3-Dioxane
  • 5-HT1A receptor agonist
  • Anti-depressant
  • Antinociceptive activity
  • Anxiolytic

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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