To better understand the role of dopamine D-4 receptor (D4R) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for D4R were discovered starting from the brain penetrant and D4R selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (6). In particular, the D4R antagonist 24, showing the highest affinity and selectivity over D2R and D3R within the series (D-2/D-4 = 8318, D-3/D-4 = 3715), and the biased ligand 29, partially activating D4R G(i)-/G(o)-protein and blocking beta-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 mu M. 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.

Highly Potent and Selective Dopamine D4 Receptor Antagonists Potentially Useful for the Treatment of Glioblastoma

Giorgioni, Gianfabio;Piergentili, Alessandro
;
Quaglia, Wilma
;
Sabbieti, Maria Giovanna;Agas, Dimitrios;Santoni, Giorgio;Del Bello, Fabio
Ultimo
2022-01-01

Abstract

To better understand the role of dopamine D-4 receptor (D4R) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for D4R were discovered starting from the brain penetrant and D4R selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (6). In particular, the D4R antagonist 24, showing the highest affinity and selectivity over D2R and D3R within the series (D-2/D-4 = 8318, D-3/D-4 = 3715), and the biased ligand 29, partially activating D4R G(i)-/G(o)-protein and blocking beta-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 mu M. 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.
2022
262
File in questo prodotto:
File Dimensione Formato  
Journal of Medicinal Chemistry, 2022 Volume 65 Issue18 pp. 12124-12139.pdf

accesso aperto

Tipologia: Versione Editoriale
Licenza: PUBBLICO - Creative Commons
Dimensione 5.58 MB
Formato Adobe PDF
5.58 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/468375
Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 10
  • ???jsp.display-item.citation.isi??? 9
social impact