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

doi:10.1021/acschemneuro.8b00677

Multitarget 1,4-Dioxane Compounds Combining Favorable D₂-like and 5-HT_1A 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

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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-HT_1A, 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-HT_1A/D₄ agonism and D₂/D₃/5-HT_2A 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-HT_1A 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-HT_1A receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation.

Original language	English (US)
Pages (from-to)	2222-2228
Number of pages	7
Journal	ACS chemical neuroscience
Volume	10
Issue number	5
DOIs	https://doi.org/10.1021/acschemneuro.8b00677
State	Published - May 15 2019
Externally published	Yes

Keywords

1,4-dioxane derivatives
dopamine receptors
multitarget agents
Parkinson's disease
schizophrenia
Serotonin receptors

ASJC Scopus subject areas

Biochemistry
Physiology
Cognitive Neuroscience
Cell Biology

Access to Document

10.1021/acschemneuro.8b00677

Cite this

Del Bello, F., Ambrosini, D., Bonifazi, A., Newman, A. H., Keck, T. M., Giannella, M., Giorgioni, G., Piergentili, A., Cappellacci, L., Cilia, A., Franchini, S., & Quaglia, W. (2019). Multitarget 1,4-Dioxane Compounds Combining Favorable D₂-like and 5-HT_1A Receptor Interactions with Potential for the Treatment of Parkinson's Disease or Schizophrenia. ACS chemical neuroscience, 10(5), 2222-2228. https://doi.org/10.1021/acschemneuro.8b00677

Multitarget 1,4-Dioxane Compounds Combining Favorable D₂-like and 5-HT_1A Receptor Interactions with Potential for the Treatment of Parkinson's Disease or Schizophrenia. / Del Bello, Fabio; Ambrosini, Dario; Bonifazi, Alessandro et al.
In: ACS chemical neuroscience, Vol. 10, No. 5, 15.05.2019, p. 2222-2228.

Research output: Contribution to journal › Article › peer-review

Del Bello, F, Ambrosini, D, Bonifazi, A, Newman, AH, Keck, TM, Giannella, M, Giorgioni, G, Piergentili, A, Cappellacci, L, Cilia, A, Franchini, S & Quaglia, W 2019, 'Multitarget 1,4-Dioxane Compounds Combining Favorable D₂-like and 5-HT_1A Receptor Interactions with Potential for the Treatment of Parkinson's Disease or Schizophrenia', ACS chemical neuroscience, vol. 10, no. 5, pp. 2222-2228. https://doi.org/10.1021/acschemneuro.8b00677

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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.",

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