Multitarget 1,4-Dioxane Compounds Combining Favorable D 2 -like and 5-HT 1A 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 2 -like, 5-HT 1A , and α 1 -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 /D 4 agonism and D 2 /D 3 /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 D 2 and as a potent full agonist at D 3 and D 4 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.