Scaffold Hybridization Strategy Leads to the Discovery of Dopamine D3 Receptor-Selective or Multitarget Bitopic Ligands Potentially Useful for Central Nervous System Disorders

In the search for novel bitopic compounds targeting the dopamine D₃ receptor (D₃R), the N-(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 D₃R-selective or multitarget ligands potentially useful for central nervous system disorders. In particular, the 6,6-diphenyl-1,4-dioxane derivative 3 showed a D₃R-preferential profile, while an interesting multitarget behavior has been highlighted for the 5,5-diphenyl-1,4-dioxane and 1,4-benzodioxane derivatives 6 and 9, respectively, which displayed potent D₂R antagonism, 5-HT_1AR and D₄R agonism, as well as potent D₃R partial agonism. They also behaved as low-potency 5-HT_2AR antagonists and 5-HT_2CR partial agonists. Such a profile might be a promising starting point for the discovery of novel antipsychotic agents.