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

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 D-like, 5-HT, and α-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/D agonism and D/D/5-HT antagonism, which may be a favorable profile for the treatment of schizophrenia. Interestingly, the 3-hydroxy derivative 8 behaved as a partial agonist at D and as a potent full agonist at D and D subtypes. In addition to its potent 5-HT 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 receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation.