Highly Potent and Selective Dopamine D 4 Receptor Antagonists Potentially Useful for the Treatment of Glioblastoma.

To better understand the role of dopamine D receptor (DR) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for DR were discovered starting from the brain penetrant and DR selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1)-one (). In particular, the DR antagonist , showing the highest affinity and selectivity over DR and DR within the series (D/D = 8318, D/D = 3715), and the biased ligand , partially activating DR G-/G-protein and blocking β-arrestin recruitment, emerged as the most interesting compounds. These compounds, evaluated for their GBM antitumor activity, induced a decreased viability of GBM cell lines and primary GBM stem cells (GSC#83), with the maximal efficacy being reached at a concentration of 10 μM. Interestingly, the treatment with both compounds and induced an increased effect in reducing the cell viability with respect to temozolomide, which is the first-choice chemotherapeutic drug in GBM.