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

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

  • ACS Chem Neurosci. 2021 Oct 6;12(19):3638-3649. doi: 10.1021/acschemneuro.1c00368.
Alessandro Bonifazi 1 2,  Amy H Newman 1,  Thomas M Keck 1 3,  Silvia Gervasoni 4,  Giulio Vistoli 4,  Fabio Del Bello 2,  Gianfabio Giorgioni 2,  Pegi Pavletić 2,  Wilma Quaglia 2,  Alessandro Piergentili 2
Affiliations

Affiliations

  • 1 Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States.
  • 2 School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, Camerino 62032, Italy.
  • 3 Department of Chemistry & Biochemistry, Department of Molecular & Cellular Biosciences, Rowan University, 201 Mullica Hill Rd, Glassboro, New Jersey 08028, United States.
  • 4 Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, Milano 20133, Italy.
PMID: 34529404 DOI: 10.1021/acschemneuro.1c00368
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.

Keywords

bitopic ligands; central nervous system disorders; docking studies; dopamine D3 receptors; multitarget compounds.

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