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

Abstract

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.

Dopamine-induced arrestin recruitment and desensitization of the dopamine D4 receptor is regulated by G protein-coupled receptor kinase-2

“…We note that some previous investigations that did not detect D 4 R-mediated arrestin recruitment used luciferase complementation (Forster et al, 2020) or fluorescence microscopy to assess redistribution of βarr2 to the plasma membrane (Spooren et al, 2010). On the other hand, some of the studies that did find evidence for such recruitment used PathHunter (Keck et al, 2019;Pirzer et al, 2019) or bioluminescent resonance energy transfer (BRET) approaches to monitor βarr2-D 4 R interactions (Sánchez-Soto et al, 2016;Lyu et al, 2019;Pavletić et al, 2022). Assay sensitivity would seem a likely explanation for these discrepancies.…”

Exploring Structural Determinants of Bias among D4 Subtype-Selective Dopamine Receptor Agonists

“…In general, and providing further motivation for the present study, the particular role of β-arrestin at the D 4 receptor is still largely unclear. While some studies found that activation of the D 4 receptor by an agonist does not elicit β-arrestin recruitment or receptor internalization, − other studies could well detect recruitment and desensitization. ,, In addition, the precise interplay of GRK2 and β-arrestin was shown to be of importance. , …”

“…Regarding the structural background of bias between G protein and β-arrestin pathways, interactions of the functionally selective ligands with the ECL2 have been described to be a major factor. , In line with these findings, Wang et al postulated that the functional selectivity of 2 at the D 4 receptor stems from an interaction between the ligand’s quinolone moiety and the Leu-187 residue in ECL2. Ligand 4 , in addition to a interaction with Leu-187, also binds in proximity to the adjacent residues Cys-185 and Arg-186, thus resulting in antagonism at the β-arrestin pathway . An interaction at a proximate site (Val-184 and Arg-186) can be observed for APH199 ( 5 ) and its closely related derivatives, resulting in partial agonism at the β-arrestin pathway with bias factors up to 26 when compared to quinpirole …”

“…After the D 4 receptor was first discovered and cloned in 1991 by Van Tol et al, and it was shown that the atypical antipsychotic clozapine binds preferentially to this receptor subtype, interest in the development of D 4 receptor antagonists for the treatment of schizophrenia dramatically increased. − Although most efforts turned out as unsuccessful, since, for example, the D 4 subtype selective ligand L-745,870 was found to be ineffective in the treatment of schizophrenia, a general interest in the development of subtype selective D 4 receptor ligands remained. Particular objectives are the treatment of addictive disorders related to cocaine, , morphine, amphetamine − or nicotine, the reduction of l -DOPA-induced dyskinesia or the targeting of glioblastoma, which could be addressed by antagonists. Subtype selective agonists, in contrast, may provide alternative options for the treatment of eating disorders, − attention deficit disorder, − erectile disfunction, − or cognitive deficits .…”

Properly Substituted Benzimidazoles as a New Promising Class of Nicotinate Phosphoribosyltransferase (NAPRT) Modulators

“…Materials and general methods for the synthesis and chemical characterization of the final compounds and intermediates are reported in the ‘ Supplementary Materials ’ and given in references [ 33 , 34 ].…”