Scaffold Hybridization Strategy Leads to the Discovery
of Dopamine D3 Receptor-Selective or Multitarget Bitopic
Ligands Potentially Useful for Central Nervous System Disorders
posted on 2021-09-16, 17:05authored byAlessandro Bonifazi, Amy H. Newman, Thomas M. Keck, Silvia Gervasoni, Giulio Vistoli, Fabio Del Bello, Gianfabio Giorgioni, Pegi Pavletić, Wilma Quaglia, Alessandro Piergentili
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-HT1AR and D4R agonism,
as well as potent D3R partial agonism. They also behaved
as low-potency 5-HT2AR antagonists and 5-HT2CR partial agonists. Such a profile might be a promising starting
point for the discovery of novel antipsychotic agents.