Search Results (16)

A series of 2- and 3-methoxyphenylpiperazine derivatives in combination with a 2-hydroxypropoxy linker and coumarins containing various substituents was synthesized and evaluated for antidepressant-like activity. Microwave-assisted synthesis was used, and the structures of all compounds were confirmed by ¹H, ¹³C NMR, and HRMS spectrometry. The affinity toward the 5-HT_1A and 5-HT_2A receptors was determined using radioligand binding assays and analyzed by molecular docking studies. Among the compounds evaluated, four demonstrated high affinity for the 5-HT_1A receptor with the following Ki values: 5-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-4,7-dimethyl-2H-chromen-2-one (5) (90 nM), 6-acetyl-5-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-4,7-dimethyl-2H-chromen-2-one (7) (90 nM), 7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl) propoxy)-4-methyl-2H-chromen-2-one (10) (87 nM), and 8-acetyl-7-(2-hydroxy-3-(4-(2-methoxy phenyl)piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (11) (96 nM), and four demonstrated high affinity for the 5-HT_2A receptor with the following Ki values: 6-acetyl-7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (2) (83 nM), 8-acetyl-7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (12) (67 nM), 7-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl) propoxy)-2H-chromen-2-one (13) (18 nM), and 7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-2H-chromen-2-one (14) (68 nM). In functional assays, 8-acetyl-7-(2-hydroxy-3-(4-(2-methoxyphenyl) piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (compound 11) exhibited a significant 5-HT_1A antagonistic profile. Computational studies revealed the structural details responsible for the high affinity of selected derivatives, which were compared to known 5HT_1A partial agonists. Full article

In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (1–15) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds 7–9. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α₁-adrenergic receptors (α₁-AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α₁-adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α_1A and α_1B, was conducted. Selected compounds were tested for their activity towards two α₁-AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds (1 and 5), which possess o-methoxyphenylpiperazine fragments, strong activity (IC₅₀ < 100 nM) was observed. Some representatives (3 and 5), which contain alkyl linker, proved selectivity towards α_1A-AR, while two compounds with 2-hydroxypropyl linker (11 and 13) to α_1B-AR. Finally, hypotensive activity was examined in rats. The most active compound (5) proved not only a lower effective dose than urapidil but also a stronger effect than prazosin. Full article

Excessive fructose consumption may lead to metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD) and hypertension. α1-adrenoceptors antagonists are antihypertensive agents that exert mild beneficial effects on the metabolic profile in hypertensive patients. However, they are no longer used as a first-line therapy for hypertension based on Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) outcomes. Later studies have shown that quinazoline-based α1-adrenolytics (prazosin, doxazosin) induce apoptosis; however, this effect was independent of α1-adrenoceptor blockade and was associated with the presence of quinazoline moiety. Recent studies showed that α1-adrenoceptors antagonists may reduce mortality in COVID-19 patients due to anti-inflammatory properties. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted anti-inflammatory, antihypertensive properties and reduced insulin resistance and visceral adiposity. In this study, we aimed to evaluate the effect of fructose consumption and treatment with α1-adrenoceptor antagonists of different classes (MH-76 and prazosin) on liver tissue of fructose-fed rats. Livers were collected from four groups (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical and histopathological studies. Both α1-adrenolytics reduced macrovesicular steatosis and triglycerides content of liver tissue and improved its antioxidant capacity. Treatment with MH-76, contrary to prazosin, reduced leucocytes infiltration as well as decreased elevated IL-6 and leptin concentrations. Moreover, the MH-76 hepatotoxicity in hepatoma HepG2 cells was less than that of prazosin. The use of α1-adrenolytics with anti-inflammatory properties may be an interesting option for treatment of hypertension with metabolic complications. Full article

D3 receptors, a key component of the dopamine system, have emerged as a potential target of therapies to improve motor symptoms across neurodegenerative and neuropsychiatric conditions. In the present work, we evaluated the effect of D3 receptor activation on the involuntary head twitches induced by 2,5-dimethoxy-4-iodoamphetamine (DOI) at behavioral and electrophysiological levels. Mice received an intraperitoneal injection of either a full D3 agonist, WC 44 [4-(2-fluoroethyl)-N-[4-[4-(2-methoxyphenyl)piperazin 1-yl]butyl]benzamide] or a partial D3 agonist, WW-III-55 [N-(4-(4-(4-methoxyphenyl)piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamide] five minutes before the intraperitoneal administration of DOI. Compared to the control group, both D3 agonists delayed the onset of the DOI-induced head-twitch response and reduced the total number and frequency of the head twitches. Moreover, the simultaneous recording of neuronal activity in the motor cortex (M1) and dorsal striatum (DS) indicated that D3 activation led to slight changes in a single unit activity, mainly in DS, and increased its correlated firing in DS or between presumed cortical pyramidal neurons (CPNs) and striatal medium spiny neurons (MSNs). Our results confirm the role of D3 receptor activation in controlling DOI-induced involuntary movements and suggest that this effect involves, at least in part, an increase in correlated corticostriatal activity. A further understanding of the underlying mechanisms may provide a suitable target for treating neuropathologies in which involuntary movements occur. Full article

The crystal structures of three salts, namely N-(4-methoxyphenyl)piperazin-1-ium ethoxybenzoate monohydrate (I), N-(4-methoxyphenyl)piperazin-1-ium methoxybenzoate monohydrate (II) and N-(4-methoxyphenyl)piperazin-1-ium hydroxybenzoate monohydrate (III), have been determined and compared. In each of them, the ionic components and the water molecules are linked by a combination of N—H···O and O—H···O hydrogen bonds to form infinite chains of edge-fused centrosymmetric rings running parallel to the [100] direction. The C—H···O, C—H···π(arene) interactions and O—H···O in (III) are responsible for the further propagation of the aforementioned chains into di-periodic layers or tri-periodic networks. From an energetic point of view, all structures are primarily di-periodic; the very strong ionic interactions determine the periodicity. For comparison purposes, quantum chemical calculations were performed to show the difference between the ionic and neutral components. The energy of the hydrogen-bonded ring motifs was also estimated. Full article

Arrhythmia, an irregular heartbeat, might be a life-threatening condition but also a risk factor for stroke or worsen the prognosis after myocardial infarction. The limited efficacy and proarrhythmic potential of the available drugs require searching for new, more effective, and safer pharmacotherapies. Studies indicate that the blockade of α₁-adrenoceptors could be effective in treating heart rhythm abnormalities. In this study, we aimed to assess the antiarrhythmic and hypotensive potential of HBK-10, a novel 2-methoxyphenylpiperazine derivative, as well as its binding to the selected adrenergic receptors. Radioligand binding studies demonstrated that HBK-10 showed a high affinity for α₁ but not for α₂ or β₁ receptors. Next, we evaluated the ability of HBK-10 to protect against an adrenaline-induced arrhythmia in rats. The compound showed potent prophylactic antiarrhythmic properties in this arrhythmia model. Notably, the compound did not show proarrhythmic potential in normotensive rats since it did not influence the ECG parameters at antiarrhythmic doses. Finally, the compound showed hypotensive properties in rats, which were not observed after coadministration with adrenaline, noradrenaline, or methoxamine, which suggests α₁-adrenolytic properties of HBK-10. Our results confirm that compounds with a 2-methoxyphenylpiperazine group show a high affinity for α₁-adrenoceptors and a significant antiarrhythmic effect. Given the promising results of our study, further evaluation of HBK-10 is necessary to unravel the mechanisms behind its pharmacological effects and evaluate the safety profile. Full article

Quinoline scaffold is one of the most intensively utilized pharmacophores in drug design because of the variety of activities demonstrated by different quinoline-based therapeutics or drug-candidates. Herein, we describe an environmentally tolerant two-step procedure as a convenient synthetic approach to novel chloroquine and hydroxychloroquine analogues. The structures of the newly synthesized compounds are estimated by ¹H NMR, ¹³C NMR, LC-MS spectrometry and IR spectroscopy. Full article

Based on previously highlighted structural features, the development of highly selective 5-HT_1A receptor inhibitors is closely linked to the incorporation of a 4-alkyl-1-arylpiperazine scaffold on them. In this paper, we present the synthesis of two new compounds bearing the 2-MeO-Ph-piperazine moiety linked via a three carbon atom linker to the amine group of 1-adamantanamine and memantine, respectively. Both were tested for their binding affinity against 5-HT_1A receptor. N-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)tricyclo[3.3.1.1^3,7]decan-1-amine fumarate (8) and N-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-3,5-dimethyl-tricylo[3.3.1.1^3,7]decan-1-amine fumarate (10) proved to be highly selective ligands towards 5-HT_1A receptor with a binding constant of 1.2 nM and 21.3 nM, respectively, while 5-carboxamidotriptamine (5-CT) (2) was used as an internal standard for this assay with a measured K_i = 0.5 nM. Full article

The increasing number of patients reporting depressive symptoms requires the design of new antidepressants with higher efficacy and limited side effects. As our previous research showed, 2-methoxyphenylpiperazine derivatives are promising candidates to fulfill these criteria. In this study, we aimed to synthesize a novel 2-methoxyphenylpiperazine derivative, HBK-10, and investigate its in vitro and in vivo pharmacological profile. After assessing the affinity for serotonergic and dopaminergic receptors, and serotonin transporter, we determined intrinsic activity of the compound at the 5-HT_1A and D₂ receptors. Next, we performed behavioral experiments (forced swim test, tail suspension test) to evaluate the antidepressant-like activity of HBK-10 in naïve and corticosterone-treated mice. We also assessed the safety profile of the compound. We showed that HBK-10 bound strongly to 5-HT_1A and D₂ receptors and presented antagonistic properties at these receptors in the functional assays. HBK-10 displayed the antidepressant-like effect not only in naïve animals, but also in the corticosterone-induced mouse depression model, i.e., chronic administration of HBK-10 reversed corticosterone-induced changes in behavior. Moreover, the compound’s sedative effect was observed at around 26-fold higher doses than the antidepressant-like ones. Our study showed that HBK-10 displayed a favorable pharmacological profile and may represent an attractive putative treatment candidate for depression. Full article

Background: Quinazoline α₁-adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α₁-adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes; however, these effects were proven to be independent of α₁-adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α₁-adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats. Methods: Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed. Results: Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307. Conclusion: MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced. Full article

Activating double mutations L858R/T790M in the epidermal growth factor receptor (EGFR) region are often observed as the cause of resistance to tyrosine kinase inhibitors (TKIs). Third-generation EGFR-TKIs, such as osimertinib and rociletinib (CO-1686), was developed to target such resistance mutations. The detection of activating L858R/T790M mutations is necessary to select sensitive patients for therapy. Hence, we aimed to develop novel radiobromine-labeled CO-1686 as a positron emission tomography (PET) imaging probe for detecting EGFR L858R/T790M mutations. Nonradioactive brominated-CO1686 (BrCO1686) was synthesized by the condensation of N-(3-[{2-chloro-5-(trifluoromethyl)pyrimidin-4-yl}amino]-5-bromophenyl) acrylamide with the corresponding substituted 1-(4-[4-amino-3-methoxyphenyl]piperazine-1-yl)ethan-1-one. The radiobrominated [⁷⁷Br]BrCO1686 was prepared through bromodestannylation of the corresponding tributylstannylated precursor with [⁷⁷Br]bromide and N-chlorosuccinimide. Although we aimed to provide a novel PET imaging probe, ⁷⁷Br was used as an alternative radionuclide for ⁷⁶Br. We fundamentally evaluated the potency of [⁷⁷Br]BrCO1686 as a molecular probe for detecting EGFR L858R/T790M using human non-small-cell lung cancer (NSCLC) cell lines: H1975 (EGFR L858R/T790M), H3255 (EGFR L858R), and H441 (wild-type EGFR). The BrCO1686 showed high cytotoxicity toward H1975 (IC₅₀ 0.18 ± 0.06 µM) comparable to that of CO-1686 (IC₅₀ 0.14 ± 0.05 µM). In cell uptake experiments, the level of accumulation of [⁷⁷Br]BrCO1686 in H1975 was significantly higher than those in H3255 and H441 upon 4 h of incubation. The radioactivity of [⁷⁷Br]BrCO1686 (136.3% dose/mg protein) was significantly reduced to 56.9% dose/mg protein by the pretreatment with an excess CO-1686. These results indicate that the binding site of the radiotracers should be identical to that of CO-1686. The in vivo accumulation of radioactivity of [⁷⁷Br]BrCO1686 in H1975 tumor (4.51 ± 0.17) was higher than that in H441 tumor (3.71 ± 0.13) 1 h postinjection. Our results suggested that [⁷⁷Br]BrCO1686 has specificity toward NSCLC cells with double mutations EGFR L858R/T790M compared to those in EGFR L858R and wild-type EGFR. However, the in vivo accumulation of radioactivity in the targeted tumor needs to be optimized by structural modification. Full article

Selective high-affinity antagonists for the dopamine D₃ receptor (D₃R) are sought for treating substance use disorders. Positron emission tomography (PET) with an effective D₃R radioligand could be a useful tool for the development of such therapeutics by elucidating pharmacological specificity and target engagement in vivo. Currently, a D₃R-selective radioligand does not exist. The D₃R ligand, N-(4-(4-(3-chloro-2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indole-2-carboxamide (BAK4-51, 1), has attractive properties for PET radioligand development, including full antagonist activity, very high D₃R affinity, D₃R selectivity, and moderate lipophilicity. We labeled 1 with the positron-emitter carbon-11 (t_1/2 = 20.4 min) in the methoxy group for evaluation as a radioligand in animals with PET. However, [¹¹C]1 was found to be an avid substrate for brain efflux transporters and lacked D₃R-specific signal in rodent and monkey brain in vivo. Full article

Based on a known pharmacophore model for 5-HT₆ receptor antagonists, a series of novel extended derivatives of the N-arylsulfonyindole scaffold were designed and identified as a new class of 5-HT₆ receptor modulators. Eight of the compounds exhibited moderate to high binding affinities and displayed antagonist profile in 5-HT₆ receptor functional assays. Compounds 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1H-indol-3-yl)ethanol (4b), 1-(1-(4-iodophenylsulfonyl)-1H-indol-3-yl)-2-(4-(2-methoxyphenyl)piperazin-1-yl)ethanol (4g) and 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-(naphthalen-1-ylsulfonyl)-1H-indol-3-yl)ethanol (4j) showed the best binding affinity (4b pK_i = 7.87; 4g pK_i = 7.73; 4j pK_i = 7.83). Additionally, compound 4j was identified as a highly potent antagonist (IC₅₀ = 32 nM) in calcium mobilisation functional assay. Full article

A series of new thiophene derivatives has been synthesized using the Gewald protocol. The acetylcholinesterase inhibition activity was assayed according to Ellman’s method using donepezil as reference. Some of the compounds were found to be more potent inhibitors than the reference. 2-(2-(4-(4-Methoxyphenyl)piperazin-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (IIId) showed 60% inhibition, compared to only 40% inhibition by donepezil. Full article

The title compound was synthesized by condensation of an oxiran imide derivative with an appropriate amine and its IR, ¹H NMR, ¹³C NMR and mass spectroscopic data are reported. The synthesized compound was evaluated for its cytotoxicity and anti-HIV-1 activity in MT-4 cells. Full article