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Abstract: An association between α1-adrenoceptor affinities, hERG K+-antagonistic properties and antiarrhythmic activities for a series of phenylpiperazine derivatives of hydantoin (2a–21a) was investigated. New compounds were synthesized and tested for their affinity for α1-adrenoceptors in radioligand binding assay using [3H]-prazosin as a selective radioligand. Antiarrhythmic activities in adrenaline- and barium chloride-induced arrhythmia models, an influence of the phenylpiperazine derivatives on the ECG-components and blood pressure were tested in vivo in normotensive rats. The hERG K+-antagonistic properties of the most potent antiarrhythmic agents were investigated in silico by the use of program QikProp. The highest α1-adrenoceptor affinity (K i =4.7nM) and the strongest antiarrhythmic activity in adrenaline induced arrhythmia (ED50 =0.1mg/kg) was found for 1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione hydrochloride (19a). The results indicated a significant correlation between α1-AR affinities (pK i) and antiarrhythmic activity (ED50) in adrenaline model (R2 =0.92, p <0.005). Influence of the examined phenylpiperazine hydantoin derivatives on hERG K+ channel, predicted by means of in silico methods, suggested their hERG K+-blocking properties. [Copyright &y& Elsevier]

Abstract: Recently we have shown that 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride (LPP1) is an antinociceptive and local anesthetic agent in rodents. Below an extended study of the pharmacological activity of LPP1 is described. In vitro LPP1 has no affinity for GABAA, opioidergic μ and serotonergic 5-HT1A receptors. The total antioxidant capacity of LPP1 (1–10mM) measured as ABTS radical cation-scavenging activity showed that LPP1 has dose-dependent antioxidant properties in vitro. Low plasma concentration of this compound detected by means of HPLC method 30min after its intraperitoneal administration suggests a rapid conversion to metabolite(s) which may be responsible for its analgesic and anticonvulsant activities in vivo. In vivo the compound''s influence on the electroconvulsive threshold and its activity in the maximal electroshock seizure test (MES) were evaluated. The results demonstrated that LPP1 had an anticonvulsant activity in the MES model (ED50 =112mg/kg) and at a dose of 50mg/kg was able to elevate the electroconvulsive threshold for 8mA as compared to the vehicle-treated mice. The analgesic activity of LPP1 was investigated in the acetic acid-induced writhing test in two groups of mice: animals with sensory C-fibers ablated, and mice with C-fibers unimpaired. It proved the potent activity of this compound in both groups (approximately 85% as compared to the vehicle-treated mice). The adverse effects of LPP1 were evaluated as acute toxicity (LD50 =747.8mg/kg) and motor coordination impairments in the rotarod and chimney tests. The results from these tests show that LPP1 at doses higher than 100mg/kg is likely to impair the motor performance of experimental animals. Concluding, LPP1 is an analgesic and anticonvulsant compound which has antioxidant properties in vitro. Further studies are necessary to assess whether the antioxidant activity and the receptor profiling demonstrated in vitro can be confirmed for its metabolite(s) that are formed in vivo. [Copyright &y& Elsevier]

Abstract: A series of N2-{2-[4-aryl(benzyl)-1-piperazinyl(piperidinyl)]ethyl}pyrrolo[3,4-d]pyridazinones 4 and related derivatives 5 were synthesized as potential analgesic agents. The structures of the new compounds were elucidated by micro, spectral and X-ray analysis. Analgesic activity of the compounds was investigated in the phenylbenzoquinone induced ‘writhing’ and ‘hot plate’ test in mice and at radioligand binding assay. At ‘writhing’ test all compounds, without exception, were more active than acetylsalicylic acid (ASA) with ED50 values ranging from 0.04 to 11 mg/kg (i.p.) (ED50 for ASA – 39.15 mg/kg). Analgesic effect at the ‘hot plate’ test was observed for three compounds 4c,e,f at the dose 3–5 times higher then that of morphine (ED50-3.39 mg/kg). At radioligand binding assay of 4c,e,f only compound 4f exhibited affinity for the μ-opioid receptors similar to that of Tramadol. The acute toxicity of the pyrrolopyridazinones 4, 5 were also studied and non toxic effect was observed at the 2000 mg/kg (5a 1420 mg/kg) i.p. dose level. On the basis of the available pharmacological data S-A relationship is discussed. The preferred conformational characteristic of 4, taken 4c as an example, was also described. [Copyright &y& Elsevier]

Abstract: The study is focused on (2-alkoxy)phenylpiperazine derivatives of 1-(2-hydroxy-3-(4-arylpiperazin-1-yl)propyl)-5,5-diphenylimidazolidine-2,4-dione with alkyl or ester substituents at N3 of hydantoin ring, as well as a new designed and synthesized series of compounds with a free N3H group or N3-acetic acid terminal fragment. The compounds were assessed on their affinity for 5-HT1A and α1-adrenoceptors and evaluated in functional bioassays for antagonistic properties. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) and DFT methods (B3LYP functional, Gaussian 0.3) were used to investigate 3D structure of the compounds. SAR analysis was based on two pharmacophore models, the one described by Barbaro et al. for α1-adenoceptor antagonist and the model of Lepailleur et al. for 5-HT1A receptor ligands. All compounds exhibited significant to moderate affinities for 5-HT1A receptors in nanomolar range (7–610nM). The highest activity (7nM) and selectivity (17.38) for 5-HT1A was observed for 1-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione (13a). Among new synthesized compounds 1-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5,5-diphenylimidazolidine-2,4-dione hydrochloride (20a) displayed the highest affinity (16.6nM) and selectivity (5.72) for α1-AR. [Copyright &y& Elsevier]

The present results indicated that tolerance to nitroglycerin (glycerin trinitrate, GTN) increased the hepatic and renal level of reactive oxygen species, malondialdehyde, and glutathione peroxidase (POx) and decreased superoxide dismutase activity, whereas non-protein thiols remained unchanged in both organs. In the liver (but not in the kidney) glutathione S-transferase (GST), catalase and rhodanese activities decreased and the sulfane sulfur level also dropped. Unlike in the liver, γ-glutamyl transpeptidase (γGT) activity in the kidney declined. On the other hand, hepatic S-nitrosothiols (SNT) rose while renal SNT declined. As no concomitant changes in the nitric oxide (NO) level were observed in either organ, the results suggested that under nitroglycerin tolerance NO was stored in the liver in the form of SNT. In conclusion, the results obtained in the liver and kidney confirm the involvement of oxidative stress in the pathomechanism of GTN tolerance, and reveal the diverse effects of this phenomenon on the γGT and GST activity and SNT level in both organs. We observed for the first time that GTN tolerance could be accompanied by the disruption of hepatic anaerobic cysteine metabolism, associated with sulfane sulfur and rhodanese activity. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel arylpiperazines bearing a 3,3-diphenylpyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs), as well as their antiarrhythmic, and antihypertensive activities. The highest affinity for the α1-AR was displayed by 1-{3-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (7), which binds with a pK i =7.28. The highest affinity for the α2-AR was shown by 1-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (5), which binds with a pK i =6.68. Compound 7 was additionally evaluated in in vitro functional tests for its affinity for α1B- and α1D-AR, which gave pA2 α1B =6.55 and pA2 α1D =7.26. Among the compounds tested, compound 7 also had the highest prophylactic antiarrhythmic activity in adrenaline-induced arrhythmia in anaesthetized rats. Its ED50 value was 1.1mg/kg (i.v.). The compounds significantly decreased systolic and diastolic pressure in normotensive anaesthetized rats at doses of 2.5–5.0mg/kg (i.v.) and their hypotensive effects lasted for longer than 1h. It was found that the introduction of two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave compounds with affinity for both α1- and α2-AR. The substitution of the 2nd position in the phenyl piperazinyl fragment of the molecule was crucial for activity. To determine detailed information concerning the structure–activity relationship, a preliminary molecular modeling study was undertaken. [Copyright &y& Elsevier]

Abstract: A series of xanthone derivatives were synthesized and examined for electrocardiographic, antiarrhythmic, hypotensive and anticonvulsant activities as well as for α1- and β1-adrenergic binding affinities. Among the investigated compounds, some of them exhibited significant antiarrhythmic and/or hypotensive activity. The data obtained via receptor binding assay are in agreement with pharmacological results and could explain antiarrhythmic and/or hypotensive activity of the newly synthesized structures. [Copyright &y& Elsevier]

Abstract: Besides other organic nitrates, nitroglycerin (glyceryl trinitrate; GTN) has been used to treat acute heart failure particularly due to ischemic heart disease. However, one of serious clinical problems of the GTN therapy, particularly a long-standing medication, is hemodynamic tolerance to GTN, manifested by the decreased therapeutic efficacy of the drug. The most recent studies have suggested that mitochondrial lipoate/dihydrolipoate system-dependent aldehyde dehydrogenase-2 plays a key role in nitric oxide release from GTN. The aldehyde dehydrogenase-2 performs three enzymatic activities of dehydrogenase, esterase and reductase. The reductase activity is responsible for bioactivation of organic nitrates, such as GTN yielding nitrite and dinitrate (1,2-GDN/1,3-GDN, ~ 8:1). In view of a large contribution of dihydrolipoic acid to stabilization and regeneration of thiol groups, necessary for the reductase activity of aldehyde dehydrogenase-2, we conducted studies aimed to determine whether lipoic acid administration to rats is able to prevent GTN tolerance. The studies were conducted on 4 groups of animals: control saline-treated, model GTN-tolerant, GTN + lipoic acid-treated, lipoic acid alone-administered groups. On the 9th day of experiment animals were given i.v. therapeutic dose of GTN. We measured in all animals systolic and diastolic blood pressure before injection of therapeutic dose of GTN into the cadual vein and during 20 min thereafter. Levels of nitric oxide and reactive oxygen species and activities of glutathione peroxidase and superoxide dismutase were assayed in the aorta, plasma and heart of all animals. In addition, levels of malondialdehyde, and non-protein thiols, and activities of glutathione S-transferase and γ-glutamyl transpeptidase were evaluated in the heart and plasma. The obtained results indicate that treatment of rats with a combination of lipoic acid and GTN can efficiently counteract GTN tolerance. [Copyright &y& Elsevier]

Abstract: In the search for new antiarrhythmic agents, some active 2-methoxyphenylpiperazine derivatives of phenytoin were obtained as a chemical modification of compound AZ-99 (3-ethyl-1-[2-hydroxy-3-(4-phenylpiperazin-1-yl)-propyl]-2,4-dioxo-5,5-diphenylimidazolidine). These compounds possessed structural properties similar to those of α1-adrenoceptor antagonists. In the present study, the affinities of the 2-methoxyphenylpiperazine derivatives (1a–3a) for α1- and α2-adrenoceptors were evaluated using radioligand ([3H]prazosin, [3H]clonidine) binding assays. In the next step, a new series of phenylpiperazine derivatives of phenytoin (4a–16a) containing 2-methoxyphenyl-, 2-ethoxyphenyl-, 2-pyridyl- or 2-furoylpiperazine moiety, as well as, various ester or alkyl substituents at 3-position of hydantoin ring were synthesized. The newly synthesized compounds were tested for their affinity to α1- and α2-adrenoceptors. They have shown affinities for α1-adrenoceptors at nanomolar to submicromolar range. Some compounds were moderately selective ligands of α1-adrenoceptors. Selected compounds (3a–5a, 7a, 13a, 14a) were also evaluated for their α1-adrenoceptor antagonistic properties in functional bioassays. A SAR study indicated that the most active compounds contain 2-alkoxyphenylpiperazine moieties and methyl or 2-methylpropionate substituent at 3-N position in hydantoin. The exchange of 2-alkoxyphenyl moiety into 2-furoyl or 2-pyridyl group significantly decreased affinities for α1-adrenoceptors. Molecular modelling results obtained using conformational analysis CONFLEX and PM5 method for geometry optimization, allowed for comparison of the spatial properties of tested compounds with pharmacophore model created by Barbaro et al. for the ideal α1-adrenoceptor antagonist. [Copyright &y& Elsevier]

Abstract: The synthesis of unsubstituted and halogen substituted 5-arylidene basic amide derivatives of imidazolidine-2,4-dione is described. Structural elucidation based on X-ray analysis was performed for four representative compounds. The effect of the studied compounds on the electrocardiogram was examined in vitro in the non-working heart perfusion test and that of an anti-arrhythmic activity in the rat coronary artery ligation-reperfusion model. The most active compound: (5Z)-(3-chloro)benzylidene-3-{2-[4-(hydroxyethyl)piperazin-1-yl]-2-oxoethyl}imidazolidine-2,4-dione has shown properties of the compounds belonging to class Ia, according to the Vaughan Williams classification. Chosen compounds evaluated in vivo were devoid of anticonvulsant and neurotoxical activity. [Copyright &y& Elsevier]

Abstract: During the search for antiarrhythmic agents among amide derivatives of phenytoin, compound 7 {3-ethyl-1-[2-hydroxy-3-(4-phenyl-piperazin-1-yl)-propyl]-2,4-dioxo-5,5-diphenyl-imidazolidine} was selected as it showed antiarrhythmic as well as antihypertensive activity. Treating this compound as a lead, new derivatives 8–19 were synthesised, differing in piperazine phenyl ring substitution (2-, 3-, 4-Cl, 2-CH3O) as well as in hydantoin N3 alkyl chain (ethyl, ethyl acetate or ethyl 2-propionate). The obtained compounds in form of hydrochlorides 7a–19a were examined for prophylactic antiarrhythmic and antihypertensive properties. Compounds containing ethyl 2-propionate moiety (17a, 18a) exhibited the highest antihypertensive properties. Water-soluble compounds, containing 2-methoxyphenylpiperazine group (11a, 19a), showed strong antiarrhythmic properties in adrenaline-induced arrhythmia; compound 9a {1-[3-(4-(3-chloro-phenyl)-piperazin-1-yl)- 2-hydroxy-propyl]- 3-ethyl-2,4-dioxo-5,5-diphenyl-imidazolidine hydrochloride} exhibited the highest antiarrhythmic activity in barium chloride arrhythmia model. [Copyright &y& Elsevier]

The aim of the present study was to investigate nitroglycerin (NTG) bioactivation pathways in the liver after various periods of its administration. We also attempted to elucidate the relationship between nitric oxide (NO) and S-nitrosothiol (SNT) levels, and concentration of nonprotein thiols (NPSH) and intensity of peroxidative processes. Intravenous injections of NTG cause an increase in NO and SNT levels in the rat liver. The same intravenous NTG injections in the rats pretreated with 5-day i.p. NTG administrations lead to a drop in the levels of the biologically active NO, SNT and NPSH, with no concomitant changes in the rate of lipid peroxidation. This indicates that after such period of nitroglycerin pretreatment, levels of pharmacologically active NO and SNT decrease. However, during longer periods of NTG administration (for 10 and 17 days) NO, SNT and NPSH concentrations remain at the control level in spite of a considerably enhanced lipid peroxidation, which indicates that tolerance did not develop. Effects of NTG bioactivation in the liver, i.e. the levels of NO and SNT released from it, after different periods of drug administration correspond with hypotensive effects, which are known to be dependent on NTG biodegradation in vascular endothelial cells. The changes in NO and SNT levels observed in the rat liver after different periods of NTG administration parallel alterations in the hypotensive effect. In conclusion, NTG treatment for 10 and 17 days does not lead to tolerance, however, a transient loss of its pharmacological activity occurs after 5-day NTG pretreatment. [ABSTRACT FROM AUTHOR]

Byline: Karolina. Pytka, Elzbieta. Zmudzka, Klaudia. Lustyk, Anna. Rapacz, Adrian. Olczyk, Adam. Galuszka, Anna. Waszkielewicz, Henryk. Marona, Jacek. Sapa, Filipek. Barbara Objectives: Xanthones are flavonoids with numerous activities, including antioxidant, [...]

γ-Aminobutyric acid (GABA) neurotransmission has a significant impact on the proper functioning of the central nervous system. Numerous studies have indicated that inhibitors of the GABA transporters mGAT1-4 offer a promising strategy for the treatment of several neurological disorders, including epilepsy, neuropathic pain, and depression. Following our previous results, herein, we report the synthesis, biological evaluation, and structure-activity relationship studies supported by molecular docking and molecular dynamics of a new series of N -benzyl-4-hydroxybutanamide derivatives regarding their inhibitory potency toward mGAT1-4. This study allowed us to identify compound 23a (N -benzyl-4-hydroxybutanamide bearing a dibenzocycloheptatriene moiety), a nonselective GAT inhibitor with a slight preference toward mGAT4 (pIC 50 = 5.02 ± 0.11), and compound 24e (4-hydroxy- N -[(4-methylphenyl)-methyl]butanamide bearing a dibenzocycloheptadiene moiety) with relatively high inhibitory activity toward mGAT2 (pIC 50 = 5.34 ± 0.09). In a set of in vivo experiments, compound 24e successively showed predominant anticonvulsant activity and antinociception in the formalin model of tonic pain. In contrast, compound 23a showed significant antidepressant-like properties in mice. These results were consistent with the available literature data, which indicates that, apart from seizure control, GABAergic neurotransmission is also involved in the pathophysiology of several psychiatric diseases, however alternative mechanisms underlying this action cannot be excluded. Finally, it is worth noting that the selected compounds showed unimpaired locomotor skills that have been indicated to give reliable results in behavioral assays. [Display omitted] • Novel inhibitors of GABA transporters mGAT1-4 were designed and synthesized. • The inhibitory potencies of all final compounds were determined for mGAT1–4 in a [3H]GABA uptake assay in HEK-293 cells. • A 4-hydroxybutanamide derivative (24e) was found to be the most potent mGAT2 inhibitor. • Compound 24e showed anticonvulsant activity in the electroconvulsive threshold and the pentylenetetrazole tests. • Compound 23a showed significant antidepressant-like properties in mice. [ABSTRACT FROM AUTHOR]

Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic, neuropathic pain. We obtained a phenoxyalkylaminoalkanol derivative, KM-416 which had previously demonstrated a significant anticonvulsant activity and had also been shown to bind to 5-HT 1A , α 2 -receptors and SERT and not to exhibit mutagenic properties. As KM-416 is a promising compound in our search for drug candidates, in the present study we further assessed its pharmacological profile (analgesic, local anesthetic, and antidepressant-like activities) accompanied with patch-clamp studies. Considering the importance of drug safety, its influence on the cardiovascular system was also evaluated. Moreover, KM-416 was subjected to forced degradation and pharmacokinetic studies to examine its stability and pharmacokinetic parameters. KM-416 revealed a significant antinociceptive activity in the tonic - the formalin test, neurogenic – the capsaicin test, and neuropathic pain model - streptozotocin-induced peripheral neuropathy. Moreover, it exerted a local anesthetic effect. In addition, KM-416 exhibited anti-depressant like activity. The results from the patch-clamp studies indicated that KM-416 can inhibit currents elicited by activation of NMDA receptors, while it also exhibited a voltage-dependent inhibition of Na+ currents. KM-416 did not influence ventricular depolarization and repolarization. Following oral administration, pharmacokinetics of KM-416 was characterized by a rapid absorption in the rat. The brain-to-plasma AUC ratio was 6.7, indicating that KM-416 was well distributed to brain. The forced degradation studies showed that KM-416 was very stable under stress conditions. All these features made KM-416 a promising drug candidate for further development against neuropathic pain and epilepsy. • KM-416 contains features characteristic for propranolol and mexiletine. • KM-416 revealed antinociceptive, local-anesthetic and antidepressant-like activity. • KM-416 is well distributed to the brain tissue. • KM-416 is very stable under the degradation conditions. • KM-416 is a promising drug candidate for epilepsy and non-epileptic conditions. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate analgesic and antiallodynic activity of four new 3-benzhydryl-pyrrolidine-2,5-dione derivatives, which demonstrated previously anticonvulsant activity in the seizure tests in mice. Analgesic activity was examined in acute (the hot plate test), tonic (the formalin test), as well as neuropathic (the oxaliplatin-induced peripheral neuropathy) pain models in mice. Moreover, potential sedative properties and hepatotoxicity were evaluated. To establish the plausible mechanism of action, in vitro assays were carried out. All tested compounds RS 34 , RS 37 , RS 48 , and RS 49 , similarly to pregabalin , were active in the second phase of formalin test, a model of tonic pain. The most promising effect was observed for compounds RS 34 , RS 48 , and RS 49 , which in a statistically significant way attenuated the nocifensive response at all tested doses 1, 10, and 30 mg/kg. Furthermore, all compounds at a dose of 30 mg/kg revealed antiallodynic activity in neuropathic pain related to chemotherapy-induced peripheral neuropathy in mice. In experimental tests on three compounds RS 34 , RS 37 and RS 48 at active doses no sedative properties were registered. In the in vitro assay the selected molecule RS 34 did not induce cytotoxic effect on hepatoma cells. The binding and functional studies did not provide firm evidence on possible mechanism of action of these derivatives. In conclusion, the tested pyrrolidine-2,5-dione derivatives with antiseizure activity exerted also analgesic and antiallodynic effects in mouse models of pain. [ABSTRACT FROM AUTHOR]

• Cholinesterase inhibition ability of fifty histamine H3 receptor ligands was assessed in vitro. • Four promising multi-target-directed ligands were discovered. • Chosen ligands displayed high drug-likeness and good blood–brain barrier penetration. • Binding mode of the most active compounds was explained by molecular docking. • Procognitive effect in passive avoidance test was revealed. In the search for new treatments for complex disorders such as Alzheimer's disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4- n -propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4- n -propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood–brain barrier penetration in test conditions. The most promising compound, A12 , chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA 2 = 8.27), inhibitory activity against both AChE (IC 50 = 13.96 μM), and BuChE (IC 50 = 14.62 μM). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice. [ABSTRACT FROM AUTHOR]