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

Abstract

To better understand the role of dopamine D ₄ receptor (D ₄R) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for D ₄R were discovered starting from the brain penetrant and D ₄R selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1 H)-one ( 6). In particular, the D ₄R antagonist 24, showing the highest affinity and selectivity over D ₂R and D ₃R within the series (D ₂/D ₄ = 8318, D ₃/D ₄ = 3715), and the biased ligand 29, partially activating D ₄R 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.