In the search for
novel bitopic compounds targeting the dopamine
D
3
receptor (D
3
R), 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 D
3
R-selective or multitarget ligands potentially useful for central
nervous system disorders. In particular, the 6,6-diphenyl-1,4-dioxane
derivative
3
showed a D
3
R-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
D
2
R antagonism, 5-HT
1A
R and D
4
R agonism,
as well as potent D
3
R partial agonism. They also behaved
as low-potency 5-HT
2A
R antagonists and 5-HT
2C
R partial agonists. Such a profile might be a promising starting
point for the discovery of novel antipsychotic agents.