Scaffold Hybridization Strategy Leads to the Discovery of Dopamine D Receptor-Selective or Multitarget Bitopic Ligands Potentially Useful for Central Nervous System Disorders.

In the search for novel bitopic compounds targeting the dopamine D receptor (DR), the -(2,3-dichlorophenyl)piperazine nucleus (primary pharmacophore) has been linked to the 6,6- or 5,5-diphenyl-1,4-dioxane-2-carboxamide or the 1,4-benzodioxane-2-carboxamide scaffold (secondary pharmacophore) by an unsubstituted or 3-F-/3-OH-substituted butyl chain. This scaffold hybridization strategy led to the discovery of potent DR-selective or multitarget ligands potentially useful for central nervous system disorders. In particular, the 6,6-diphenyl-1,4-dioxane derivative showed a DR-preferential profile, while an interesting multitarget behavior has been highlighted for the 5,5-diphenyl-1,4-dioxane and 1,4-benzodioxane derivatives and , respectively, which displayed potent DR antagonism, 5-HTR and DR agonism, as well as potent DR partial agonism. They also behaved as low-potency 5-HTR antagonists and 5-HTR partial agonists. Such a profile might be a promising starting point for the discovery of novel antipsychotic agents.