2. Academic Validation
  3. New Arylpiperazines as Potent and Selective Dopamine D4 Receptor Ligands Potentially Useful to Treat Glioblastoma

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

  • J Med Chem. 2025 Apr 10;68(7):7441-7458. doi: 10.1021/acs.jmedchem.4c03150.
Federica Matteucci 1,  Pegi Pavletić 1 2,  Alessandro Bonifazi 3,  Fabio Del Bello 1,  Gianfabio Giorgioni 1,  Alessandro Piergentili 1,  Consuelo Amantini 4,  Laura Zeppa 4,  Emanuela Sabato 5,  Giulio Vistoli 5,  Rian Garland 6,  Hideaki Yano 6,  Monica Castagna 7,  Valerio Mammoli 7,  Loredana Cappellacci 1,  Alessia Piergentili 1,  Wilma Quaglia 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via Madonna delle Carceri (ChIP), 62032 Camerino, Italy.
  • 2 Faculty of Biotechnology and Drug Development, University of Rijeka, Radmile Matejcic 2, 51000 Rijeka, Croatia.
  • 3 Department of Pharmacology and Toxicology, Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch, Galveston, Texas 77555, United States.
  • 4 School of Biosciences and Veterinary Medicine, Immunopathology and Molecular Medicine Unit, University of Camerino, via Madonna delle Carceri 9, 62032 Camerino, Italy.
  • 5 Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milano, Italy.
  • 6 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States.
  • 7 Center for Drug Discovery and Development-DMPK, Aptuit, an Evotec company, via A. Fleming, 4, 37135 Verona, Italy.
PMID: 40156554 DOI: 10.1021/acs.jmedchem.4c03150
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 9 and 10, 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 9 with a naphthyl group. Indeed, α-naphthyl derivative 15 proved to have four times higher affinity for D4R than lead 9, whereas β-naphthyl compound 16 was about tenfold more selective for D4R than 9. 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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