Scaffold Hybridization Strategy Leads to the Discovery of Dopamine D3Receptor-Selective or Multitarget Bitopic Ligands Potentially Useful for Central Nervous System Disorders
Articolo
Data di Pubblicazione:
2021
Citazione:
Scaffold Hybridization Strategy Leads to the Discovery of Dopamine D3Receptor-Selective or Multitarget Bitopic Ligands Potentially Useful for Central Nervous System Disorders / A. Bonifazi, A.H. Newman, T.M. Keck, S. Gervasoni, G. Vistoli, F. Del Bello, G. Giorgioni, P. Pavletic, W. Quaglia, A. Piergentili. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - 12:19(2021 Sep 16), pp. 3638-3649. [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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
bitopic ligands; central nervous system disorders; docking studies; dopamine D; 3; receptors; multitarget compounds;
Elenco autori:
A. Bonifazi, A.H. Newman, T.M. Keck, S. Gervasoni, G. Vistoli, F. Del Bello, G. Giorgioni, P. Pavletic, W. Quaglia, A. Piergentili
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