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. 2019 May 15;10(5):2222-2228.
doi: 10.1021/acschemneuro.8b00677. Epub 2019 Jan 9.

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  1 , Dario Ambrosini  1 , Alessandro Bonifazi  2 , Amy H Newman  2 , Thomas M Keck  2   3 , Mario Giannella  1 , Gianfabio Giorgioni  1 , Alessandro Piergentili  1 , Loredana Cappellacci  1 , Antonio Cilia  4 , Silvia Franchini  5 , Wilma Quaglia  1
Affiliations

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 et al. ACS Chem Neurosci. .

Abstract

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.

Keywords: 1,4-dioxane derivatives; Parkinson’s disease; Serotonin receptors; dopamine receptors; multitarget agents; schizophrenia.

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Figures

Figure 1.
Figure 1.
Chemical structure and biological profile of SLV-308 (pardoprunox).
Figure 2.
Figure 2.
Chemical structures of compounds 1–13. The phenoxyethylamine fragments are in bold.
Scheme 1 –
Scheme 1 –
a) CH3OCH2CH2OH, reflux, 5 h; b) HCOOH/MeOH, Pd/C, 24 h.
See this image and copyright information in PMC

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