HBK-14 and HBK-15 do not influence blood pressure, lipid profile, glucose level, or liver enzymes activity after chronic treatment in rats

Older and even new antidepressants cause adverse effects, such as orthostatic hypotension, hyper- or hypoglycemia, liver injury or lipid disorders. In our previous experiments we showed significant antidepressant- and anxiolytic-like activities of dual 5-HT1A and 5-HT7 antagonists with α1-adrenolitic properties i.e. 1-[(2,6-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15). Here, we evaluated the influence of chronic administration of HBK-14 and HBK-15 on blood pressure (non-invasive blood pressure measurement system for rodents), lipid profile (total cholesterol, low density lipoproteins-LDL, high density lipoproteins-HDL, triglycerides), glucose level, and liver enzymes activity (aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase). We determined potential antihistaminic (isolated guinea pig ileum) and antioxidant properties (ferric reducing ability of plasma-FRAP, non-protein thiols-NPSH, stable free radical diphenylpicrylhydrazyl-DPPH) cytotoxicity. Our experiments revealed that HBK-14 and HBK-15 did not influence blood pressure, lipid profile, glucose level or liver enzymes activity in rats after 2-week treatment. We also showed that none of the compounds possessed antioxidant or cytotoxic properties at antidepressant- and anxiolytic-like doses. HBK-14 and HBK-15 very weakly blocked H1 receptors in guinea pig ileum. Positive results of our preliminary experiments on the safety of HBK-14 and HBK-15 encourage further studies concerning their effectiveness in the treatment of depression and/or anxiety disorders

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

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

Aryl-1,3,5-triazine ligands of histamine H4H_{4} receptor attenuate inflammatory and nociceptive response to carrageen, zymosan and lipopolysaccharide

Objective and design Histamine $H_{4}$ receptor ($H_{4}R$) offers a great potential for new therapeutic strategies for the treatment of inflammation-based diseases. The aim of this study is to present the pharmacological profile of two recently synthesized ligands of $H_{4}R$ with particular reference to their anti-inflammatory and analgesic activity. Materials and subjects We used mice and rats in the in vivo tests. We also used murine RAW 264.7 cells and isolated guinea-pig ileum in in vitro test. Treatments In the in vivo tests, animals were pre-treated with the increasing doses of investigated compounds (12.5, 25 and 50 mg/kg) and reference compounds: JNJ7777120 (25 mg/kg), indomethacin (10 mg/kg). Macrophages were pre-treated with two concentrations of tested compounds 100 and 10 $\mu$M. Methods We examined anti-inflammatory and analgesic effects of the new $H_{4}R$ antagonists in the in vivo models of inflammation induced by carrageenan or zymosan. We assessed the level of cAMP and release of cytokines, ROS and NO in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Moreover, we assessed the affinity of the investigated compounds for histamine $H_{1}$ receptor in functional studies. Results Both investigated compounds reduced paw edema, mechanical and thermal hyperalgesia in the carrageenaninduced acute inflammation. Moreover, administration of the investigated compounds resulted in decreased granulocyte influx and attenuated nociceptive reaction in the zymosan-induced peritonitis model. In the same model of inflammation, the investigated compounds reduced vascular permeability; however, this effect was observed only after the highest applied dose. Furthermore, the test compounds had no impact on cell viability in the experiments on RAW 264.7 macrophages. In these cells, stimulated with LPS, the test compounds decreased reactive oxygen species (ROS) production. They increased the cellular concentration of cAMP and attenuated the production of inflammatory cytokines such as $TNF\alpha$ and $IL-1\beta$. All results were comparable to those obtained for the reference compound JNJ7777120 with the exception of the impact on NO production. Nevertheless, this effect was similar to that obtained for the other reference compound rolipram, which is a phosphodiesterase 4 (PDE 4) inhibitor. Further experiments revealed that both of the investigated compounds possessed relatively low affinity for histamine H$_{1}$ receptor and do not inhibit the activity of the PDE 4B1 enzyme. In addition, all the effects of the investigated compounds in in vivo experiments were observed at doses that did not cause neurologic deficits in rotarod test and did not reduce spontaneous locomotor activity. Conclusions Our results demonstrate the anti-inflammatory and analgesic activity of the new aryl-1,3,5-triazine derivatives, which are primarily $H_{4}R$-dependent

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

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