Synthesis, anticonvulsant and antinociceptive activity of new hybrid compounds : derivatives of 3-(3-methylthiophen-2-yl)-pyrrolidine-2,5-dione

The present study aimed to design and synthesize a new series of hybrid compounds with pyrrolidine-2,5-dione and thiophene rings in the structure as potential anticonvulsant and antinociceptive agents. For this purpose, we obtained a series of new compounds and evaluated their anticonvulsant activity in animal models of epilepsy (maximal electroshock (MES), psychomotor (6 Hz), and subcutaneous pentylenetetrazole (scPTZ) seizure tests). To determine the mechanism of action of the most active anticonvulsant compounds (3, 4, 6, 9), their influence on the voltage-gated sodium and calcium channels as well as GABA transporter (GAT) was assessed. The most promising compound 3-(3-methylthiophen-2-yl)-1-(3-morpholinopropyl)pyrrolidine-2,5-dione hydrochloride (4) showed higher ED50 value than those of the reference drugs: valproic acid (VPA) and ethosuximide (ETX) (62.14 mg/kg vs. 252.7 mg/kg (VPA) in the MES test, and 75.59 mg/kg vs. 130.6 mg/kg (VPA) and 221.7 mg/kg (ETX) in the 6 Hz test, respectively). Moreover, in vitro studies of compound 4 showed moderate but balanced inhibition of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Additionally, the antinociceptive activity of the most active compounds (3, 4, 6, 9) was also evaluated in the hot plate test and writhing tests, and their hepatotoxic properties in HepG2 cells were also investigated. To determine the possible mechanism of the analgesic effect of compounds 3, 6, and 9, the affinity for the TRPV1 receptor was investigated

Tridentate hydrazido-hydrazones vanadium complexes : synthesis, properties and biological activity

Nine new vanadium complexes, with tridentate Schiff base ligand based on 3,5-di-tertbutyl-2-hydroxybenzaldehyde and different hydrazides, are described and characterized. The X-ray crystal structure of complex 8 shows distorted octahedral geometry of vanadium, with ONO ligand in equatorial position. The tridentate Schiff base ligand forms six membered and five-membered chelate rings at the V(V) acceptor center, with the corresponding bite angles being 82.97(9)˚ and 74.48(9)˚. The molecules are gathered by means of intermolecular OH...N hydrogen bond and layered by π...π interactions involving the pyridine and phenolate rings. Such interactions expand the structure along the crystallographic a axis. The complexes were characterized by the elemental analyses, IR, UV-Vis, EPR spectroscopy, cyclic voltammetry, thermogravimetry and magnetic susceptibility measurements. The stabilization role of co-ligands is discussed. The cytotoxicity versus HepG2 hepatocytes and inhibition of human recombinant PTP1B was studied

Potentiation of adipogenesis and insulinomimetic effects of novel vanadium complex (N'-[(E)-(5-bromo-2-oxophenyl)methylidene]-4-methoxybenzohydrazide)oxido(1,10-phenanthroline)vanadium(IV) in 3T3-L1 cells

Recent research on the action of vanadium compounds shows its important effect on adipogenesis processes and adipocyte function. On the basis of previous screening tests in cellular models, the novel vanadium complex (N′-[(E)-(5-bromo-2-oxophenyl)methylidene]4-methoxybenzohydrazide)oxido(1,10-phenanthroline)vanadium(IV) was selected for this study. This complex exhibits potent inhibition of tyrosine phosphatases, and differences in the degree of inhibition were observed particularly for phosphatases. A significant increase in intracellular lipid accumulation and proliferative effect on 3T3-L1 preadipocytes confirmed the ability of this complex to enhance adipogenesis. The insulinomimetic activity of the tested complex was also demonstrated in fully differentiated 3T3-L1 adipocytes, in which glucose utilization was potentiated. The obtained results support the hypothesis that vanadium complexes show promising possibilities for use as new therapeutic strategies for the treatment of type 2 diabetes

A comparison of the anorectic effect and safety of the alpha_{2}-adrenoceptor ligands guanfacine and yohimbine in rats with diet-induced obesity

The search for drugs with anorectic activity, acting within the adrenergic system has attracted the interest of researchers. Partial α2-adrenoceptor agonists might offer the potential for effective and safe treatment of obesity. We compared the effectiveness and safety of α2-adrenoceptor ligands in reducing body mass. We also analyzed if antagonist and partial agonists of α2-adrenoceptor--yohimbine and guanfacine--act similarly, and determined which course of action is connected with anorectic activity. We tested intrinsic activity and effect on the lipolysis of these compounds in cell cultures, evaluated their effect on meal size, body weight in Wistar rats with high-fat diet-induced obesity, and determined their effect on blood pressure, heart rate, lipid profile, spontaneous locomotor activity, core temperature and glucose, as well as glycerol and cortisol levels. Both guanfacine and yohimbine showed anorectic activity. Guanfacine was much more effective than yohimbine. Both significantly reduced the amount of intraperitoneal adipose tissue and had a beneficial effect on lipid profiles. Decreased response of α2A-adrenoceptors and partial stimulation of α2B-receptors seem to be responsible for the anorectic action of guanfacine. The stimulation of α1-adrenoceptors by guanfacine is responsible for cardiovascular side effects but may also be linked with improved anorexic effect. α1-adrenoceptor blockade is connected with the side effects of yohimbine, but it is also associated with the improvement of lipid profiles. Guanfacine has been approved by the Food and Drug Administration (FDA) to treat hypertension and conduct disorder, but as it reduces body weight, it is worth examining its effectiveness and safety in models of obesity

6-Acetyl-5-hydroxy-4,7-dimethylcoumarin derivatives : design, synthesis, modeling studies, 5-HT1A, 5-HT2A and D2 receptors affinity

Molecular docking studies using appropriate 5-HT$_{1A}$, 5-HT$_{2A}$ and D$_{2}$ receptors models were used to design sixteen new 5-hydroxycoumarin derivatives with piperazine moiety (3–18). The microwave radiation have been used to synthesize them and their structures have been confirmed using mass spectrometry, $^{1}$H and $^{13}$C NMR. All newly prepared derivatives were evaluated for their 5-HT$_{1A}$, 5-HT$_{2A}$ and D$_{2}$ receptor affinity. Seven of the synthesized derivatives showed very high affinities to 5-HT$_{1A}$ receptor (3–4.0 nM, 6–4.0 nM, 7–1.0 nM, 9–6.0 nM, 15–4.3 nM, 16–1.0 nM, 18–3.0 nM) and one of them showed high affinities to 5-HT$_{2A}$ receptor (16–8.0 nM). In the case of the D$_{2}$ receptor none of the tested derivatives showed high affinity. Compounds 7 and 16 were identified as potent antagonists of the 5-HT$_{1A}$ receptor as shown by the [35S]GTPcS binding assay but they didn’t show any antidepressant effect at the single dose tested (10 mg/kg) in the tail suspension tests

Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1A receptor partial agonists

Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Serotonin 5-HT1A receptor is considered as an interesting target of antidepressant therapy. In the present study, the intrinsic activity at different signaling pathways coupled to serotonin 5-HT1A receptor, antidepressant-like and pharmacokinetic properties, and the safety profile of two novel imidazopurine-2,4-dione derivatives, namely compounds AZ-853 (8-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-1,3-dimethyl-1H- imidazo[2,1-f]purine-2,4(3H,8H)-dione) and AZ-861 (1,3-dimethyl-8-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), were studied in animal models through in vitro and in vivo experiments. We demonstrated that AZ-853 and AZ-861, which structurally differ by one substituent and its placement in the phenyl ring, showed varied functional, pharmacological, and pharmacokinetic properties as well as side effect profiles. AZ-861 exhibited stronger agonistic action in all functional assays. After acute and repeated administration in mice, both compounds showed antidepressant-like activity in the forced swim test, which was partially mediated by 5-HT1A receptor activation. AZ-853 showed a more potent antidepressant-like effect, presumably due to its better penetration into brain structures. Both compounds did not show anticholinergic properties, but after repeated administration, they induced weak sedation and lipid metabolism disturbances without affecting serum glucose level. The stronger α1-adrenolytic effect of AZ-853 is responsible for decreased systolic blood pressure, and in contrast to AZ-861, AZ-853 induced weight gain in mice. The interesting comparative pharmacological profiles of AZ-853 and AZ-861 encourage to conduct further experiments to fully understand their mechanisms and differences in action

Milk-Derived Carbon Quantum Dots: Study of Biological and Chemical Properties Provides Evidence of Toxicity

Carbon dots (CDs) are carbon-based zero-dimensional nanomaterials that can be prepared from a number of organic precursors. In this research, they are prepared using fat-free UHT cow milk through the hydrothermal method. FTIR analysis shows C=O and C-H bond presence, as well as nitrogen-based bond like C-N, C=N and –NH2 presence in CDs, while the absorption spectra show the absorption band at 280 ± 3 nm. Next, the Biuret test was performed, with the results showing no presence of unreacted proteins in CDs. It can be said that all proteins are converted in CDs. Photo luminance spectra shows the emission of CDs is 420 nm and a toxicity study of CDs was performed. The Presto Blue method was used to test the toxicity of CDs for murine hippocampal cells. CDs at a concentration of 4 mg/mL were hazardous independent of synthesis time, while the toxicity was higher for lower synthesis times of 1 and 2 h. When the concentration is reduced in 1 and 2 h synthesized CDs, the cytotoxic effect also decreases significantly, ensuring a survival rate of 60–80%. However, when the synthesis time of CDs is increased, the cytotoxic effect decreases to a lesser extent. The CDs with the highest synthesis time of 8 h do not show a cytotoxic effect above 60%. The cytotoxicity study shows that CDs may have a concentration and time–dependent cytotoxic effect, reducing the number of viable cells by 40%

Antidepressant- and anxiolytic-like effects of new dual 5-HT_{1A} and 5-HT_{7} antagonists in animal models

The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14-FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15-FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds