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

[Image: see text] 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(1H)-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.