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.

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

Del Bello, Fabio;Ambrosini, Dario;Bonifazi, Alessandro;Giannella, Mario;Giorgioni, Gianfabio
;
Piergentili, Alessandro;Cappellacci, Loredana;Quaglia, Wilma
2019-01-01

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.
2019
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ACS Chem Neurosci., 2019 vol. 10(5) pp. 2222–2228.pdf

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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/426504
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