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 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.