Multitarget 1,4-Dioxane Compounds Combining Favorable D2-like and 5-HT1A Receptor Interactions with Potential for the Treatment of Parkinson's Disease or Schizophrenia

Fabio Del Bello, Dario Ambrosini, Alessandro Bonifazi, Amy H. Newman, Thomas M. Keck, Mario Giannella, Gianfabio Giorgioni, Alessandro Piergentili, Loredana Cappellacci, Antonio Cilia, Silvia Franchini, Wilma Quaglia

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11 Scopus citations


The effect of methoxy and hydroxy substitutions in different positions of the phenoxy moiety of the N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-phenoxyethan-1-amine scaffold on the affinity/activity for D2-like, 5-HT1A, and α1-adrenoceptor subtypes was evaluated. Multitarget compounds with suitable combinations of dopaminergic and serotoninergic profiles were discovered. In particular, the 2-methoxy derivative 3 showed a multitarget combination of 5-HT1A/D4 agonism and D2/D3/5-HT2A antagonism, which may be a favorable profile for the treatment of schizophrenia. Interestingly, the 3-hydroxy derivative 8 behaved as a partial agonist at D2 and as a potent full agonist at D3 and D4 subtypes. In addition to its potent 5-HT1A receptor agonism, such a dopaminergic profile makes 8 a potential multitarget compound for the treatment of Parkinson's disease (PD). Indeed, the activation of 5-HT1A receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation.

Original languageEnglish (US)
Pages (from-to)2222-2228
Number of pages7
JournalACS chemical neuroscience
Issue number5
StatePublished - May 15 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


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