In the search for novel bitopic compounds targeting the dopamine D 3 receptor (D 3 R), the N -(2,3-dichlorophenyl)piperazine nucleus (primary pharmacophore) has been linked to the 6,6- or 5,5-diphenyl-1,4-dioxane-2-carboxamide or the 1,4-benzodioxane-2-carboxamide scaffold (secondary pharmacophore) by an unsubstituted or 3-F-/3-OH-substituted butyl chain. This scaffold hybridization strategy led to the discovery of potent D 3 R-selective or multitarget ligands potentially useful for central nervous system disorders. In particular, the 6,6-diphenyl-1,4-dioxane derivative 3 showed a D 3 R-preferential profile, while an interesting multitarget behavior has been highlighted for the 5,5-diphenyl-1,4-dioxane and 1,4-benzodioxane derivatives 6 and 9 , respectively, which displayed potent D 2 R antagonism, 5-HT 1A R and D 4 R agonism, as well as potent D 3 R partial agonism. They also behaved as low-potency 5-HT 2A R antagonists and 5-HT 2C R partial agonists. Such a profile might be a promising starting point for the discovery of novel antipsychotic agents.
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.
In this paper the benzo-cracking approach was applied to the potent sigma1 (σ1) receptor antagonist 1 to afford the less conformationally constrained 1,3-dioxane derivatives 2 and 3. To evaluate the effect of the increase of the distance between the two hydrophobic structural elements that flank the basic function, the cis and trans diastereomers of 4 and 5 were also prepared and studied. Compounds 2 and 3 showed affinity values at σ1 receptor significantly higher than that of the lead compound 1. In particular, 3 displayed unprecedented selectivity over σ2 receptor, the phencyclidine site of the NMDA receptor, and opioid receptor subtypes, as well as over dopamine transporter. Docking results supported the structure-activity relationship studies. Due to its interesting biological profile, derivative 3, selected for an in vivo study in a validated preclinical model of binge eating, was able to counteract the overeating of palatable food only in binging-rats, without affecting palatable food intake in the control group and anxiety-like and depression-related behaviors in female rats. This result strengthened the involvement of σ1 receptor in the compulsive-like eating behavior and supported σ1 receptor as a promising target for the management of eating disorders.
Liver cytosolic fatty acid binding protein (FABP) represents the intracellular equivalent to extracellular serum albumin, participating in the intracellular transport of long-chain fatty acids. In this study we observed the effect of increasing and decreasing FABP levels on hepatocyte [3H]palmitate uptake in male Sprague-Dawley rats. We also were interested to determine whether uptake, from either the unbound or unbound and protein-bound fractions, was fundamentally different at the different FABP levels. FABP levels were modified by hypophysectomy and clofibrate treatment (50 mg/100 g body weight for 10 days). Results showed that the [3H]palmitate clearance rates paralleled the 54% decrease and 73% increase in FABP levels in hypophysectomy and clofibrate-treated animals, respectively. In the presence of 2 and 20 microM albumin, hepatocyte clearance rates of unbound [3H]palmitate from hypophysectomized animals (0.16+/-0.01 and 0.64+/-0.01 mL x s(-1) x 10(-6) cells, respectively) were significantly lower (p<0.01) than those of the sham group (0.30+/-0.02 and 1.00+/-0.06 mL x s(-1) x 10(-6) cells, respectively). However, the unbound [3H]palmitate clearance rates from the clofibrate-treated group (0.39+/-0.04 and 1.18+/-0.12 mL x s(-1) x 10(-6) cells) were significantly higher (p<0.01) than the control group (0.29+/-0.02 and 0.81+/-0.05 mL x s(-1) x 10(-6) cells) for 2 and 20 microM albumin, respectively. To investigate whether uptake was fundamentally different between the hypophysectomized and clofibrate-treated groups, we expressed the clearance rates as enhancement factors, i.e., EF = CL20 microM/CL2microM. No statistical difference was observed between EF of the hypophsectomized (3.8+/-0.4) and EF of the clofibrate-treated (3.1+/-0.3) groups, suggesting that the extracted ligand originated from similar fractions.
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