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

18 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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