Scaffold Hybridization Strategy Leads to the Discovery of Dopamine D3Receptor-Selective or Multitarget Bitopic Ligands Potentially Useful for Central Nervous System Disorders

Alessandro Bonifazi, Amy H. Newman, Thomas M. Keck, Silvia Gervasoni, Giulio Vistoli, Fabio Del Bello, Gianfabio Giorgioni, Pegi Pavletić, Wilma Quaglia, Alessandro Piergentili

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3638-3649
Number of pages12
JournalACS chemical neuroscience
Volume12
Issue number19
DOIs
StatePublished - Oct 6 2021

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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