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

Abstract

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.

Highly Potent and Selective Dopamine D4 Receptor Antagonists Potentially Useful for the Treatment of Glioblastoma

“…The pharmacological profile of compounds 7–33 as oxalate salts was evaluated by radioligand binding assays with human recombinant D 2 -like receptor subtypes stably expressed in HEK293T cells using the [ 3 H] N -methylspiperone, a high-affinity D 2 -like antagonist, as radioligand to label DRs, following previously described protocols. , …”

“…The protein structures were prepared as previously described. 36 , 37 The ligands were simulated in their protonated state and their 3D structure was optimized by using the VEGA suite of programs. 46 Docking simulations were performed by using PLANTS 47 and focusing the searches within a 10 Å radius sphere around the co-crystallized ligand.…”

“…Radioligand competition binding experiments were conducted as previously described. , Test compounds were freshly dissolved in 30% DMSO and 70% H 2 O to a stock concentration of 10 mM. Each test compound was then diluted into 10 half-log serial dilutions using a 30% DMSO vehicle.…”

“…Docking simulations involved the resolved D 4 R structure in complex with nemonapride (PDB Id: 5WIU) as well as the resolved D 2 R structure in complex with risperidone (PDB Id: 6CM4). The protein structures were prepared as previously described. , The ligands were simulated in their protonated state and their 3D structure was optimized by using the VEGA suite of programs . Docking simulations were performed by using PLANTS and focusing the searches within a 10 Å radius sphere around the co-crystallized ligand.…”

Recent advances in dopamine D2 receptor ligands in the treatment of neuropsychiatric disorders

“…On the other hand, D 4 R antagonistic properties may be used for the treatment of substance use disorders and l ‐DOPA‐induced dyskinesias 59,454,456–462 . Given abundant evidence, some scientific groups have sought to create selective D 2 R, 463,464 D 3 R, 465–485 or D 4 R 456,486–488 ligands, which can be useful tools to probe the roles of D 2 ‐like receptor subtypes in vivo and could potentially lead to new pharmacotherapeutics for the management of a variety of disorders. For better traceability of ligand selectivity, we would like to introduce a so‐called selectivity factor.…”