New Arylpiperazines as Potent and Selective Dopamine D4 Receptor Ligands Potentially Useful to Treat Glioblastoma

The dopamine D4 receptor (D4R) has recently been proposed as an emerging target for treating glioblastoma (GBM). In this article, new piperazine ligands, analogues of the potent and selective D4R lead compounds <b>9</b> and <b>10</b>, were prepared and evaluated for their affinity at D2-like receptor subtypes. The most promising results were obtained by replacing the N4-phenyl terminal of <b>9</b> with a naphthyl group. Indeed, α-naphthyl derivative <b>15</b> proved to have four times higher affinity for D4R than lead <b>9</b>, whereas β-naphthyl compound <b>16</b> was about tenfold more selective for D4R than <b>9</b>. These compounds behaved as D4R antagonists in both Gi/Go activation and β-arrestin2 recruitment assays. Interestingly, both decreased cell viability dose-dependently and altered the cell cycle of U87 MG, T98G, and U251 MG human GBM cell lines after 48 h treatment, inducing an increase in ROS levels and time-dependent mitochondrial depolarization.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-03-29
DOI
https://doi.org/10.1021/acs.jmedchem.4c03150
Citations
3
Primary Topic
Receptor Mechanisms and Signaling
Type
article
Field-Weighted Citation Impact
2.42
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article

New Arylpiperazines as Potent and Selective Dopamine D4 Receptor Ligands Potentially Useful to Treat Glioblastoma

Valerio Mammoli, Loredana Cappellacci, Monica Castagna, Alessandro Bonifazi et al.
3 citations
Journal of Medicinal Chemistry
Receptor Mechanisms and Signaling
2.42
article

New Arylpiperazines as Potent and Selective Dopamine D4 Receptor Ligands Potentially Useful to Treat Glioblastoma

Valerio Mammoli, Loredana Cappellacci, Monica Castagna, Alessandro Bonifazi, Fabio Del Bello, Giulio Vistoli, Consuelo Amantini, Laura Zeppa, Wilma Quaglia, Pegi Pavletić, Gianfabio Giorgioni, A. Piergentili, Hideaki Yano, Emanuela Sabato, Alessandro Piergentili, Federica Matteucci, Rian Garland
article en
3 citations

Abstract

The dopamine D4 receptor (D4R) has recently been proposed as an emerging target for treating glioblastoma (GBM). In this article, new piperazine ligands, analogues of the potent and selective D4R lead compounds <b>9</b> and <b>10</b>, were prepared and evaluated for their affinity at D2-like receptor subtypes. The most promising results were obtained by replacing the N4-phenyl terminal of <b>9</b> with a naphthyl group. Indeed, α-naphthyl derivative <b>15</b> proved to have four times higher affinity for D4R than lead <b>9</b>, whereas β-naphthyl compound <b>16</b> was about tenfold more selective for D4R than <b>9</b>. These compounds behaved as D4R antagonists in both Gi/Go activation and β-arrestin2 recruitment assays. Interestingly, both decreased cell viability dose-dependently and altered the cell cycle of U87 MG, T98G, and U251 MG human GBM cell lines after 48 h treatment, inducing an increase in ROS levels and time-dependent mitochondrial depolarization.

Journal of Medicinal ChemistryVol. 68(7)
Università di Camerino (IT), University of Rijeka (HR), University of Milan (IT), Drug Discovery Laboratory (Norway) (NO), Aptuit (Italy) (IT), The University of Texas Medical Branch at Galveston (US), Universidad del Noreste (MX)
Zero hunger
Openalex Percentile: Top 12%
Receptor Mechanisms and Signaling
2.42
DOISourceOpenAlex
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