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

To better understand the role of dopamine D 4 receptor (D 4 R) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for D 4 R were discovered starting from the brain penetrant and D 4 R selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1 H )-one ( 6 ). In particular, the D 4 R antagonist 24 , showing the highest affinity and selectivity over D 2 R and D 3 R within the series (D 2 /D 4 = 8318, D 3 /D 4 = 3715), and the biased ligand 29 , partially activating D 4 R G i -/G o -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 24 and 29 induced an increased effect in reducing the cell viability with respect to temozolomide, which is the first-choice chemotherapeutic drug in GBM.