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A simple, highly sensitive, and selective differential pulse voltammetry method for the determination of α-lipoic acid (LA) in pharmaceutical preparations was developed and validated. The method is based on a quasi-reversible, diffusion-controlled, one-electron anodic oxidation of LA on a boron-doped diamond electrode (BDDE) in a McIlvaine (citrate-phosphate, C-PB) buffer solution at pH 3.0. For the first time, this environment was used for LA determination. A linear calibration curve was obtained within the concentration range 5.82 × 10−8 to 4.00 × 10−4 mol L−1 with a correlation coefficient of 0.9999. The limits of detection was estimated to be 1.94 × 10−8 mol L−1, which is one of the lowest values characteristic of voltammetric and chromatographic methods of LA determination. The proposed procedure is sensitive, accurate, and precise. Its utility was demonstrated in the determination of LA in pharmaceuticals without the need for its separation from the matrices. The results were comparable to those obtained by high performance liquid chromatography reference method and were in good accordance with the once declared by manufacturers. Thus, our method can be considered as an alternative to the dominant chromatographic determinations of α-LA in real samples.

Aim of the study was evaluation of anxiolytic, antidepressant, anticonvulsant and analgesic activity in a series of a consistent group of compounds. A series of eleven new N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives has been obtained. Their affinity towards 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, D2 and α1 receptors has been assessed, and then functional assays were performed. The compounds were evaluated in mice, i.p. for their antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as – at higher doses – for anticonvulsant potential (MES) and neurotoxicity (rotarod). Two compounds (3, 6) were also evaluated for their analgesic activity in neuropathic pain models (streptozocin test, oxaliplatin test) and they were found active against allodynia in diabetic neuropathic pain at 30 mg/kg. Among the compounds, anxiolytic-like, anticonvulsant or analgesic activity was observed but antidepressant-like activity was not. One of the two most interesting compounds is 1-{2-[2-(2,4,6-trimethylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine dihydrochloride (9), exhibiting anxiolytic and anticonvulsant activity in mice, i.p. 30 min after administration (at 2.5 mg/kg and ED50 = 26.33 mg/kg, respectively), which can be justified by the receptor profile: 5-HT1A Ki = 5 nM (antagonist), 5-HT7 Ki = 70 nM, α1 Ki = 15 nM, D2 Ki = 189 nM (antagonist). Another interesting compound is 1-[3-(2,4,6-trimethylphenoxy)propyl]-4-(4-methoxyphenyl)piperazine dihydrochloride (3), exhibiting anxiolytic, anticonvulsant and antiallodynic activity in mice, i.p., 30 min after administration (at 10 mg/kg, ED50 = 23.50 mg/kg, at 30 mg/kg, respectively), which can be related with 5-HT1A weak antagonism (Ki = 146 nM), or other possible mechanism of action, not evaluated within presented study. Additionally, for the most active compound in the four-plate test (7), molecular modeling was performed (docking to receptors 5-HT1A, 5-HT2A, 5-HT7, D2 and α1A).

Unlike majority of current antidepressants, HBK-15-a 5-HT1A and 5-HT7 receptor antagonist - showed memory-enhancing properties. In this study, we aimed to further characterize pharmacological profile of HBK-15 and investigate its antidepressant- and anxiolytic-like activity in the mouse model of unpredictable chronic mild stress. We used sucrose consumption test, forced swim test and elevated plus maze test as behavioral endpoints. We also evaluated the influence of HBK-15 on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the hippocampus and prefrontal cortex, as well as body weight, relative adrenal glands weight and plasma corticosterone level in the stressed mice. We utilized LC/MS/MS method to determine HBK-15 concentration in plasma and brain. We evaluated pharmacokinetic profile and distribution to brain of HBK-15 (2.5mg/kg) after intravenous (i.v.) and intraperitoneal (i.p.) administration in CD-1 mice. HBK-15 (2.5mg/kg but not 1.25mg/kg) and fluoxetine (10mg/kg) protected stressed mice from anhedonic-, depressive- and anxiety-like behaviors, decreases in the BDNF and NGF levels in the hippocampus and prefrontal cortex, increases in plasma corticosterone levels and relative adrenal glands weight. The pharmacokinetic analysis demonstrated a rapid absorption of HBK-15 after i.p. administration (tmax=5min), a short half-life (t0.5=74min), large volume of distribution (Vss=3.7L/kg) and bioavailability after i.p. administration equal 25%. HBK-15 administered i.v. and i.p. significantly penetrated brain. Our results suggest that the blockade of serotonergic 5-HT1A and 5-HT7 receptors might be beneficial in the treatment of depressive disorders with cognitive dysfunction.

Searching for CNS active cyclic amines derivatives containing heterocyclic xanthone core we designed and synthesized a set of fourteen novel 2- or 4-methylxanthone substituted by alkyl- or aryl-piperazine moieties. The compounds were evaluated in vivo for their potential antidepressant-like activity (in the forced swim test) and anxiolytic-like activity (four-plate test) and their inhibitory effect against rat 5-HT2 receptor was checked. The pharmacokinetic analysis of active compounds done by a non-compartmental approach have shown a rapid absorption of all studied molecules from intraperitoneal cavity and good penetration the blood-brain barrier after i.p. administration with brain to plasma ratios varied from 2.8 to 31.6. Genotoxicity and biotransformation of active compounds were studied. Compound 19 interactions with major classes of GPCRs, uptake systems and ion channels were tested and results indicated that it binds to 5-HT2A, 5-HT2B receptors and sodium channels.

Over the last few decades, depression has become one of the major public health problems in our society. This problem is connected not only with morbidity, but also with treatment, specifically with the effectiveness of the therapy as well as the concomitant side effects of available antidepressants. Major depressive disorder is a complex clinical entity, including different molecular mechanisms and neurological processes. This complexity is a challenge for scientists seeking to discover an innovatory antidepressant drug with multiple and complementary mechanisms of action. In this review, we discuss the role of melatonin, neurokinin, neurotrophic tyrosine kinase and glucocorticoid receptors in depression and antidepressant-like effects.

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.