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Many essential similarities between the behavior and arrangement of biological structures and liquid crystals can be found. Moreover, some of biomacromolecules, such as DNA, are shown to exhibit lyotropic liquid crystalline phases both in vitro and in vivo . In this study, we used natural DNA concentration condition to form DNA liquid crystal (LC) phases as a simplified in vitro model of DNA self-ordering in cells. Due to the increasing interest in the use of nanoparticles as optical markers, we investigated possible applications of silver-doped gold nanoclusters (AuAgNCs) for one- and two-photon imaging in condensed DNA samples. We studied the influence of NCs doping on the DNA LC properties and the distribution of NCs within the liquid crystalline matrix. Depending on the type of DNA liquid crystalline phase we observed different emission patterns of AuAgNCs correlated with the degree of DNA ordering. [ABSTRACT FROM AUTHOR]

A series of 10 aminoalkanol derivatives of 5‐chloro‐2‐ or 5‐chloro‐4‐methylxanthone was synthetized and evaluated for anticonvulsant properties (MES test, mice, intraperitoneal) and compared with neurotoxicity rotarod test (NT, mice, i.p.). The best results both in terms of anticonvulsant activity and protective index value were obtained for 3: 5‐chloro‐2‐([4‐hydroxypiperidin‐1‐yl]methyl)‐9H‐xanthen‐9‐one hydrochloride. Compounds: 1–3, 7 and 10 revealed ED50 values in MES test: 42.78, 31.64, 25.76, 46.19 and 52.50 mg/kg b.w., respectively. 3 showed 70% and 72% of inhibition control specific binding of sigma‐1 (σ1) and sigma‐2 (σ2) receptor, respectively. 3 exhibited also antinociceptive activity at dose 2 mg/kg b.w. after chronic constriction injury in mice. 1, 3, 7 and 10 were evaluated on gastrointestinal flora and proved safe. In genotoxicity test (UMU‐Chromotest) compounds 1, 7 and 10 proved safe at dose 150–300 μg/ml. The pharmacokinetic analysis showed rapid absorption of all studied molecules from the digestive tract (tmax = 5–30 min). The bioavailability of the compounds ranged from 6.6% (1) to 16% (10). All studied compounds penetrate the blood–brain barrier with brain to plasma ratios varied from 4.15 (3) to 7.6 (compound 7), after i.v. administration, and from 1 (7) to 5.72 (3) after i.g. administration. [ABSTRACT FROM AUTHOR]

Forty new aminoalkanol derivatives with potential anticonvulsant activity were designed and synthesized. In vivo studies (mice, intraperitoneal administration) showed anticonvulsant activity (maximal electroshock seizure test, MES test) of nineteen compounds, (ED50 values and protective indices PI ranging 22.62–78.30 mg/kg b.w. and 1.78–4.25, respectively). Compounds 30 (R,S‐1‐((2‐(2‐(2‐chloro‐5‐methylphenoxy)ethoxy)ethyl)amino)propan‐2‐ol), 31 (R,S‐2‐((2‐(2‐(2‐chloro‐5‐methylphenoxy)ethoxy)ethyl)amino)propan‐1‐ol) and 33 (S enantiomer of 31) showed relatively low ED50 values (26.45–34.26 mg/kg b.w.) accompanied by PI indexes above 3. Compounds 30 and 31 were investigated in terms of mechanism of action (5‐HT1A receptors binding assay and in silico database screening) and safety against gastrointestinal flora (both compounds proved safe). An integral part of the study was also a comprehensive structure‐activity relationship, including current and previously obtained results for aminoalkanol derivatives. [ABSTRACT FROM AUTHOR]

Abstract: A series of 17 new aminoalkanol derivatives of 6-methoxy- or 7-chloro-2-methylxanthone as well as 6-methoxy-4-methylxanthone was synthesized and evaluated for anticonvulsant activity. All compounds were verified in mice after intraperitoneal (ip) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scMet) induced seizures as well as neurotoxicity assessment. Eleven of the tested substances showed protection against electrically evoked seizures in the majority of the tested mice at the dose of 100mg/kg. Additionally, one was effective at the dose of 30mg/kg. Five substances were active at the dose of 300mg/kg or at the dose of 100mg/kg in the minority of the tested mice. The most promising compound revealed ED50 value of 47.57mg/kg in MES (mice, ip, 1h after administration) and at the same time its TD50 was evaluated as above 400mg/kg. Those values gave PI (calculated as TD50/ED50) of more than 8.41. Three other synthesized xanthone derivatives also proved to act as anticonvulsants and showed ED50 values in MES test (mice, ip) ranged 80–110mg/kg. Results were quite encouraging and suggested that in the group of xanthone derivatives new potential anticonvulsants might be found. [Copyright &y& Elsevier]

The aroxyalkylaminoalcohol derivatives are a group of compounds known for their pharmacological action. The crystal structures of four new xylenoxyaminoalcohol derivatives having anticonvulsant activity are reported, namely, 2‐{[2‐(2,6‐dimethylphenoxy)ethyl]amino}‐1‐phenylethan‐1‐ol, C18H23NO2, 1, the salt N‐[2‐(2,6‐dimethylphenoxy)ethyl]‐1‐hydroxy‐1‐phenylethan‐2‐aminium 3‐hydroxybenzoate, C18H24NO2+·C7H5O3−, 2, and two polymorphs of the salt (R)‐N‐[2‐(2,6‐dimethylphenoxy)ethyl]‐1‐hydroxy‐1‐phenylethan‐2‐aminium chloride, C18H24NO2+·Cl−, 3 and 3p. Both polymorphs crystallize in the space group P21212 and each has two cations and two anions in the asymmetric unit (Z′ = 2). The molecules in the polymorphs show differences in their molecular conformations and intermolecular interactions. The crystal packing of neutral 1 is dominated by intermolecular O—H...N hydrogen bonds, resulting in the formation of one‐dimensional chains. In the crystal structures of the salt forms (2, 3 and 3p), each protonated N atom is engaged in a charge‐assisted hydrogen bond with the corresponding anion. The protonation of the N atom also influences the conformation of the molecular linker between the two aromatic rings and changes the orientation of the rings. The crystal packing of the salt forms is dominated by intermolecular O—H...O hydrogen bonds, resulting in the creation of chains and rings. Structural studies have been enriched by the calculation of Hirshfeld surfaces and the corresponding fingerprint plots. [ABSTRACT FROM AUTHOR]

[Display omitted] Six amino derivatives of xanthone were obtained via chemical synthesis. Biochemical studies revealed their SIRT2 inhibitory activity ranging from 48.5 % (compound 4 , 5-chloro-2-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-9H-xanthen-9-one hydrochloride) to 93.2 % (compound 3 , 5-chloro-2-(((2-methoxyphenethyl)amino)methyl)-9H-xanthen-9-one hydrochloride). The structure–activity analysis showed favourable properties of secondary amines relative to tertiary piperazine derivatives. The tested compounds do not possess additional SIRT1 activating activity and no antioxidant activity (DPPH in vitro assay). Comprehensive analysis of the lipophilicity of the obtained compounds was also performed. For compound 3 potential molecular targets and similar active compounds were predicted in order to facilitate further research in this group of compounds. [ABSTRACT FROM AUTHOR]

Ten new xanthone derivatives have been designed and synthesized for their potential antibacterial activity. All compounds have been screened against Staphylococcus epidermidis strains ATCC 12228 and clinical K/12/8915. The highest antibacterial activity was observed for compound 3: 5‐chloro‐2‐((4‐(2‐hydroxyethyl)piperazin‐1‐yl)methyl)‐9H‐xanthen‐9‐one dihydrochloride, exhibiting MIC of 0.8 µg/ml against ATCC 12228 strain, compared to linezolid (0.8 µg/ml), ciprofloxacin (0.2 µg/ml) or trimethoprim and sulfamethoxazole (0.8 µg/ml). For the most active compound 3, genotoxicity assay with use of Salmonella enterica serovar Typhimurium revealed safety in terms of genotoxicity at concentration 75 µg/ml and antibacterial activity against Salmonella at all higher concentrations. A final in silico prediction of skin metabolism of compound 3 seems promising, indicating stability of the xanthone moiety in the metabolism process. [ABSTRACT FROM AUTHOR]

Four crystal structures of 2‐amino‐N‐(dimethylphenoxyethyl)propan‐1‐ol derivatives, characterized by X‐ray diffraction analysis, are reported. The free base (R,S)‐2‐amino‐N‐[2‐(2,3‐dimethylphenoxy)ethyl]propan‐1‐ol, C13H21NO2, 1, crystallizes in the space group P21/n, with two independent molecules in the asymmetric unit. The hydrochloride, (S)‐N‐[2‐(2,6‐dimethylphenoxy)ethyl]‐1‐hydroxypropan‐2‐aminium chloride, C13H22NO2+·Cl−, 2c, crystallizes in the space group P21, with one cation and one chloride anion in the asymmetric unit. The asymmetric unit of two salts of 2‐picolinic acid, namely, (R,S)‐N‐[2‐(2,3‐dimethylphenoxy)ethyl]‐1‐hydroxypropan‐2‐aminium pyridine‐2‐carboxylate, C13H22NO2+·C6H4NO2−, 1p, and (R)‐N‐[2‐(2,6‐dimethylphenoxy)ethyl]‐1‐hydroxypropan‐2‐aminium pyridine‐2‐carboxylate, C13H22NO2+·C6H4NO2−, 2p, consists of one cation and one 2‐picolinate anion. Salt 1p crystallizes in the triclinic centrosymmetric space group P, while salt 2p crystallizes in the space group P41212. The conformations of the amine fragments are contrasted and that of 2p is found to have an unusual antiperiplanar arrangement about the ether group. The crystal packing of 1 and 2c is dominated by hydrogen‐bonded chains, while the structures of the 2‐picolinate salts have hydrogen‐bonded rings as the major features. In both salts with 2‐picolinic acid, the specific R12(5) hydrogen‐bonding motif is observed. Structural studies have been enriched by the generation of fingerprint plots derived from Hirshfeld surfaces. [ABSTRACT FROM AUTHOR]

Aminoalkanol derivatives have attracted much interest in the field of medicinal chemistry as part of the search for new anticonvulsant drugs. In order to study the influence of the methyl substituent and N‐oxide formation on the geometry of molecules and intermolecular interactions in their crystals, three new examples have been prepared and their crystal structures determined by X‐ray diffraction. 1‐[(2,6‐Dimethylphenoxy)ethyl]piperidin‐4‐ol, C15H23NO2, 1, and 1‐[(2,3‐dimethylphenoxy)ethyl]piperidin‐4‐ol, C15H23NO2, 2, crystallize in the orthorhombic system (space groups P212121 and Pbca, respectively), with one molecule in the asymmetric unit, whereas the N‐oxide 1‐[(2,3‐dimethylphenoxy)ethyl]piperidin‐4‐ol N‐oxide monohydrate, C15H23NO3·H2O, 3, crystallizes in the monoclinic space group P21/c, with one N‐oxide molecule and one water molecule in the asymmetric unit. The geometries of the investigated compounds differ significantly with respect to the conformation of the O—C—C linker, the location of the hydroxy group in the piperidine ring and the nature of the intermolecular interactions, which were investigated by Hirshfeld surface and corresponding fingerprint analyses. The crystal packing of 1 and 2 is dominated by a network of O—H...N hydrogen bonds, while in 3, it is dominated by O—H...O hydrogen bonds and results in the formation of chains. [ABSTRACT FROM AUTHOR]

Epilepsy and neuropathic pain are frequent neurological disorders with pathomechanism based on abnormal neuronal discharges. Secondary tissue impairment observed after traumatic brain injury is also connected with neuronal dysfunction. Those three neurological disorders are ineffectively treated with currently available pharmacotherapy options so great effort is made in searching for new effective drugs. Four N -(E)-cinnamoyl (cinnamamide) derivatives of aminoalkanols: S -(2 E)- N -(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (1), R , S -(2 E)-3-(4-chlorophenyl)- N -(1-hydroxybutan-2-yl)prop-2-enamide (2), R , S -(2 E)-3-(4-chlorophenyl)- N -(2-hydroxypropyl)prop-2-enamide (3), (2 E)-3-(4-chlorophenyl)- N -(4-hydroxycyclohexyl)prop-2-enamide (4) were evaluated in vivo and in vitro for anticonvulsant, neuroprotective and/or analgesic activity. In intravenous metrazol seizure threshold test compounds 1 – 3 did not show pro-convulsive effect but proved anticonvulsant potential. In corneal kindled mice model the tested compounds showed beneficial anticonvulsant properties with ED 50 of 36.8 mg/kg for 1 , 25.7 mg/kg for 2 , and 51.1 mg/kg for 3. Compound 2 tested in vitro in spontaneously bursting rat hippocampal slice model significantly reduced burst rate. Compounds 1 and 2 did not decrease lesion volume in acute model of traumatic brain injury. In formalin test of hyperalgesia in mice, compound 1 was active in the acute phase of the test, while compound 4 caused reduction of the time of licking of the affected paw by approx. 88% during the acute phase and 100% during the inflammatory phase. In rat sciatic ligation model of neuropathic pain, compound 1 significantly increased the paw withdrawal threshold starting from one hour after oral administration and the activity continued up to six hours. Reported here four N -(E)-cinnamoyl derivatives of aminoalkanols possess promising activity as anticonvulsant and/or analgesic agents. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate antifungal activity in a diverse group of chlorine‐containing xanthone and phenoxyethyl amine derivatives – and to select the most promising compounds for further studies. The antifungal efficacy of 16 compounds was tested with qualitative and quantitative methods against both reference and clinical strains of dermatophytes, moulds and yeasts. The disc‐diffusion method has demonstrated that from 16 tested compounds, 7 possess good antifungal activity against dermatophytes and/or moulds while none of them has shown good efficacy against yeasts or bacterial strains. The most active compounds (2, 4, 10, 11, 12, 15, 16) were tested quantitatively by broth dilution method to obtain MIC values. The MIC values against dermatophytes ranged from 8 to 64 μg/ml. Compound 2 was the most active one against dermatophytes (MIC50 and MIC90 were 8 μg/ml). The MIC values for moulds ranged from 16 to 256 μg/ml. Compound 4 was the most active one against moulds, with MIC50 and MIC90 values amounting to 32 μg/ml. Among the tested compounds, compound 4 (derivative of xanthone) was the most active one and expressed good antifungal efficacy against clinical strains of dermatophytes and moulds. However, another xanthone derivative (compound 2) was the most active and selective against dermatophytes. The selected chlorine derivatives of xanthone and phenoxyethyl amines were evaluated in vitro against dermatophytes, moulds and yeasts. We observed that only simple amine derivatives of xanthones and phenoxyethyl derivatives of pyridinyl‐ or pyrimidinylpiperazine exhibited promising antifungal activity. The most active compound (4) showed a broad spectrum of activity, being active against all 22 clinical strains tested, with MIC values ranging from 8 to 32 μg/ml. [ABSTRACT FROM AUTHOR]

A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α 1 -(compound 2 and 8 ), β -(compounds 1 , 3 , 4 , 7 ), α 1 / β -(compounds 5 and 6 ) adrenoceptors. Furthermore, compound 7 , the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the α 1 -adrenoceptor-independent mechanisms involved in the vasorelaxant properties of two non-quinazoline α 1 -adrenoceptors antagonists (MH-76 and MH-79). Endothelium intact and endothelium denuded rat aorta was contracted with 1 μM phenylephrine to plateau, and the vasodilatory effect of MH-76 and MH-79 was examined in the absence or presence of inhibitors of the different signal transduction pathways. cGMP concetration was measured in rat aorta (enzyme immunoassay kit). In human aortic endothelial cells (HAEC) NO production was examined using a DAF-FM DA fluorescent indicator, whereas in human aortic smooth muscle cells the influence of the title compounds on K + efflux was evaluated. The vasorelaxant effect of MH-76 and MH-79 was attenuated by endothelium removal, N ω -Nitro- l -arginine methyl ester (L-NAME) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) pretreatment to the level characteristic for α 1 -adrenoreceptor blocking activity. In addition, the MH-76 and MH-79 induced relaxation was reduced by K + channels blockers. In endothelium intact rat aorta, MH-76 and MH-79 caused an increase in cGMP level, whereas in HAEC they increased NO generation. In contrast, the reference, quinazoline based α 1 -antagonist prazosin, did not influence NO production. Our findings suggest that the mechanisms underlying the vasodilatory properties of non-quinazoline based α 1 -adrenoceptors antagonists MH-76 and MH-79 involve not only α 1 -adrenoceptor blocking activity but also the activation of the endothelial NO–cGMP signalling pathway and the subsequent opening of K + channels. Our studies show that such double mechanism of action is superior to pure α 1 -adrenoceptor blockade, and may be considered as a promising alternative for the prevention and treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Aminoalkanol and aroxyalkyl derivatives are known as potential anticonvulsants. Two new salts, namely bis{(R,S)‐N‐[2‐(2,6‐dimethylphenoxy)ethyl]‐1‐hydroxypropan‐2‐aminium} succinate (1s), C13H22NO2+·0.5C4H4O42−, and bis{(S)‐(+)‐N‐[2‐(2,6‐dimethylphenoxy)ethyl]‐1‐hydroxypropan‐2‐aminium} succinate (2s), C13H22NO2+·0.5C4H4O42−, have been prepared and characterized by single‐crystal X‐ray diffraction. The N atoms are protonated by proton transfer from succinic acid. Salt 1s crystallizes in the space group P21/n with one cation and half an anion in the asymmetric unit across an inversion centre, while (2s) crystallizes in the space group P21 with four cations and two anions in the asymmetric unit. The hydroxy group of the cation of 1s is observed in two R/S disorder positions. The crystals of these two salts display similar supramolecular architectures (i.e. two‐dimensional networks), built mainly by intermolecular N+—H…Oδ− and O—H…Oδ− hydrogen bonds, where `δ−' represents a partial charge. The succinate anions are engaged in hydrogen bonds, not only with protonated N atoms, but also with hydroxy groups. [ABSTRACT FROM AUTHOR]

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-HT 1A , 5-HT 2A , 5-HT 6 , 5-HT 7 , D 2 and α 1 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 ED 50  = 26.33 mg/kg, respectively), which can be justified by the receptor profile: 5-HT 1A K i  = 5 nM (antagonist), 5-HT 7 K i  = 70 nM, α 1 K i  = 15 nM, D 2 K i  = 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, ED 50  = 23.50 mg/kg, at 30 mg/kg, respectively), which can be related with 5-HT 1A weak antagonism (K i  = 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-HT 1A , 5-HT 2A , 5-HT 7 , D 2 and α 1A ). [ABSTRACT FROM AUTHOR]

Serotonin (5-HT) and adrenaline acting at platelet 5-HT 2A -serotoninergic and α 2 -adrenergic receptors are involved in platelet aggregation. We have evaluated the antagonistic potency at 5-HT 2A , α 2A –, and α 2B -adrenoceptors as well as an anti-aggregation effect of aroxyalkyl derivatives of 2-methoxyphenylpiperazine and compared them with ketanserin, sarpogrelate, prazosin, yohimbine and ARC239 (2-[2-[4-(o-methoxyphenyl)-piperazin-1-yl]-ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione). Functional bioassays at cells expressing human receptors, revealed studied compounds to be moderate antagonists of 5-HT 2A and α 2 -adrenoceptors, with around 2–7 times stronger antagonistic effect at α 2B subtype than α 2A subtype. Further, studied compounds inhibited 5-HT 2A -mediated contraction in isolated rat aortic rings and 5-HT vasopressor response in rat in vivo. Studied compounds inhibited collagen stimulated whole rat blood aggregation with compound MH-77 (1-[(2,3-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride) being more potent than sarpogrelate or yohimbine. They also inhibited 5-HT/adrenaline-, amplified ADP- or collagen- induced platelet aggregation. Simultaneous, moderate blockade of 5-HT 2A serotonin and α 2 -adrenergic receptors is effective in preventing aggregation and could constitute alternative antiplatelet therapy. [ABSTRACT FROM AUTHOR]

Most antidepressants lower seizure threshold, which might be due to the modulation of serotonergic neurotransmission. Here, we investigated the effects of two 5-HT 1A , 5-HT 7 and 5-HT 3 antagonists, i.e., 1-(2-(2-(2,6-dimethylphenoxy)ethoxy)ethyl)-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-{2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15), with antidepressant- and anxiolytic-like properties, on seizure thresholds in three acute seizure tests, i.e., the intravenous pentylenetetrazole, maximal electroshock seizure threshold (MEST), and 6-Hz corneal stimulation test in mice. We also evaluated their affinity for voltage-gated sodium channels. Our results indicate that HBK-14 increased seizure thresholds in three seizure tests in mice, while HBK-15 was active in the MEST and 6-Hz tests. None of the compounds affected neuromuscular strength or motor coordination at active doses. We showed that both compounds had high affinity for voltage-dependent sodium channels, which combined with the influence on 5-HT 1A , 5-HT 7 and 5-HT 3 receptors, might underlie their anticonvulsant effects. Since most antidepressants lower the seizure threshold, the fact that both compounds with potent antidepressant-like activity, increased or had no influence on seizure threshold is worth investigating. [ABSTRACT FROM AUTHOR]

This in vitro study was designed to examine the effect of some newly synthesized aminoalcanolic derivatives of xanthone (I, II) and aroxyalkyl derivatives of 2-methoxyphenylpiperazine (III, IV) having cardiovascular activity on the haemorheological parameters of RBCs from healthy individuals and patients with chronic venous disease. Additionally, the influence of compounds I-IV on some RBCs associated enzymes such as acetylcholinesterase (Ache), glucose-6-phosphate dehydrogenase (G6PD) and glutathione reductase (GR) as well as glutathione (GSH) content were determined in vitro in RBCs from healthy subjects. The study showed that compounds I, III and IV significantly increased RBCs deformability. Moreover, both xanthone derivatives reduced RBCs aggregation and diminished RBCs aggregates strength in all RBCs groups. Compounds II and III significantly improved Ache activity, whereas compounds I and II increased G6PD and GR activity and GSH level. In conclusion, compounds I, III and IV, which significantly improved RBCs deformability in vitro, may facilitate the passage of blood in the vascular system. Additionally, compounds I and II which inhibit RBCs aggregates formation in vitro may contribute to more rapid degradation of red blood cell aggregates in circulating blood. [ABSTRACT FROM AUTHOR]

Unlike majority of current antidepressants, HBK-15–a 5-HT 1A and 5-HT 7 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 (2.5 mg/kg) after intravenous ( i.v. ) and intraperitoneal ( i.p. ) administration in CD-1 mice. HBK-15 (2.5 mg/kg but not 1.25 mg/kg) and fluoxetine (10 mg/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 (t max = 5 min), a short half-life (t 0.5 = 74 min), large volume of distribution (V ss = 3.7 L/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-HT 1A and 5-HT 7 receptors might be beneficial in the treatment of depressive disorders with cognitive dysfunction. [ABSTRACT FROM AUTHOR]

5-HT and 5-HT receptor ligands might have antidepressant-like properties and improve cognitive function. We previously reported significant antidepressant- and anxiolytic-like effects of two dual 5-HT and 5-HT receptor antagonists in various behavioral tests in rodents. As a continuation of our previous experiments, in this study we aimed to investigate whether chronic administration of 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) caused antidepressant-like effects and elevated serotonin levels in the murine hippocampus. We also evaluated cholinolytic properties and the influence of acute administration of both compounds on cognitive function in mice. To assess antidepressant-like properties and the influence on learning and memory we used forced swim test and step-through passive avoidance task in mice, respectively. Both compounds showed antidepressant-like properties and significantly elevated serotonin levels in the hippocampus after chronic treatment (HBK-14 - 2.5 mg/kg; HBK-15 - 0.625 and 1.25 mg/kg). HBK-15 administered chronically antidepressant-like activity at lower dose (0.625 mg/kg) than the dose active after acute treatment (1.25 mg/kg). None of the compounds affected locomotor activity of mice. HBK-15 possessed very weak cholinolytic properties, whereas HBK-14 did not show any effect on muscarinic receptors. Only HBK-15 (0.625 mg/kg) presented memory-enhancing properties and ameliorated cognitive impairments caused by scopolamine (1 mg/kg). Our results indicate that 5-HT and 5-HT antagonists might have potential in the treatment of depression and possess positive influence on cognitive function. [ABSTRACT FROM AUTHOR]

A series of twenty two ( E )- N- cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH 3 or 2-CH 3 was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S -(2 E )- N -(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide ( 5 ) (ED 50 MES = 42.56, ED 50 scPTZ = 58.38, ED 50 6-Hz 44 mA = 42.27 mg/kg tested in mice after intraperitoneal ( i.p .) administration); R , S -(2 E )-3-(4-chlorophenyl)- N -(1-hydroxybutan-2-yl)prop-2-enamide ( 6 ) (ED 50 MES = 53.76, ED 50 scPTZ = 90.31, ED 50 6-Hz 44 mA = 92.86 mg/kg mice, i.p .); and R , S -(2 E )-3-(4-chlorophenyl)- N -(2-hydroxypropyl)prop-2-enamide ( 11 ) (ED 50 MES = 55.58, ED 50 scPTZ = 102.15, ED 50 6-Hz 44 mA = 51.27 mg/kg mice, i.p .). Their structures and configurations were confirmed by crystal X-ray diffraction method. The structure-activity studies among the tested series showed that chlorine atom in position para or methyl group in position ortho of phenyl ring were beneficial for anticonvulsant activity. Methyl group in position para of phenyl ring decreased anticonvulsant activity in reported series of cinnamamide derivatives. [ABSTRACT FROM AUTHOR]

Objectives: Xanthones are flavonoids with numerous activities, including antioxidant, antidepressant-, or anxiolytic-like. Therefore, the aim of our study was to determine antidepressant- and anxiolytic-like properties of four xanthone derivatives (3-chloro- 5-[(4-methylpiperazin-1-yl)methyl]-9H-xanthen-9-one dihydrochloride [HBK-5], 6-methoxy-2-[(4-methylpiperazin-1-yl) methyl]-9H-xanthen-9-one dihydrochloride, 2-[(4-benzylpiperazin-1-yl) methyl]-6-methoxy-9H-xanthen-9-one dihydrochloride, 2-{[4-(2-methoxyphenyl) piperazin-1-yl] methyl}-9H-xanthen-9-one hydrochloride), as well as the influence on cognitive and motor function of active compounds, using animal models. Materials and Methods: To determine the antidepressant-like activity, we used forced swim test (FST) and tail suspension test (TST) in mice. We evaluated anxiolytic-like properties in the four-plate test in mice. We studied the influence on cognitive and motor function in passive avoidance step-through and chimney tests, respectively. Results: The antidepressant-like activity (in both FST and TST) showed only HBK-5. Moreover, the compound was also active in the four-plate test, which suggests that it possessed anxiolytic-like properties. HBK-5 did not cause any cognitive and motor deficits in mice at antidepressant- and anxiolytic-like doses. Conclusions: HBK-5 may have potential in the treatment of depression or anxiety disorders, but this issue needs further studies. [ABSTRACT FROM AUTHOR]

Since serotonin (5-HT) is strongly involved in the etiology and pathophysiology of depression, the development of new antidepressants is still based on the serotonergic system. The complexity of serotonergic system provides an opportunity for the development of compounds with multiple and complementary mechanism of action. This study describes serotonin receptor profile, functional characterization, and pharmacological in vivo evaluation of new aroxyalkyl derivatives of 2-methoxyphenylpiperazine. The obtained results allowed for the identification of compound 3 , (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride), a partial 5-HT 1A receptor agonist, and 5-HT 2A receptor antagonist, with high affinity toward 5-HT 7 receptors, showing antidepressant- and anxiolytic-like properties. Moreover, 5-HT 1A receptor activation is crucial for the antidepressant-like activity of compound 3 . The rest of the compounds (except compounds 1 and 9 ) showed antidepressant but not anxiolytic-like properties, which did not result from 5-HT 1A receptors activation. Furthermore, the compounds are 5-HT 1A and weak 5-HT 3 receptors antagonists, and some of them 5-HT 2A antagonists. Moreover, none of the studied compounds impaired motor coordination at antidepressant-like doses. Since the studied compounds exhibited activity in behavioral assays and interacted with various receptors, the results of our experiments are very promising and require further studies. [ABSTRACT FROM AUTHOR]

Adequate control of seizures remains an unmet need in epilepsy. In order to identify new anticonvulsant agents, a series of N - trans -cinnamoyl derivatives of selected aminoalkanols was synthetized. The compounds were obtained in the reaction of N -acylation carried out in a two-phase system. The substances were tested in animal models of seizures induced either electrically (maximal electroshock – MES; 6-Hz test) or chemically, by subcutaneous injection of pentetrazol (scPTZ). Neurotoxicity was determined by the rotarod test. Lipophilicity of the active compounds, expressed as R M0 , was determined by reversed-phase thin layer chromatography and it ranged from 1.390 to 2.219. From among the tested series of compounds, R,S -( E )- N -(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide ( 1 ) and R,S -( E )- N -(2-hydroxypropyl)-3-phenylprop-2-enamide ( 3 ) exhibited the best anticonvulsant activity. Compound 1 , when administered to mice by intraperitoneal ( i.p. ) injection, showed the ED 50 values of 86.6, 60.9, and 109.6 mg/kg in the MES, 6-Hz, and scPTZ tests, respectively. For compound 3 , the ED 50 values were found to be 47.1 mg/kg in MES and 77.1 mg/kg in scPTZ (mice, i.p .). The distances measured in crystals of compound 1 were: 7.99 Å – from the phenyl ring to the hydroxyl group in the amide moiety, 5.729 Å – from the phenyl ring to the amide group, and 3.112 Å – from the amide group to the hydroxyl group in the amide moiety. The reported compounds did not exhibit mutagenic potential when assayed in the Ames test. Compounds 1 and 3 did not affect viability and morphology of human hepatocellular carcinoma cells (HepG2). [ABSTRACT FROM AUTHOR]

Xanthone derivatives have been shown to posses many biological properties. Some of them act within the central nervous system and show neuroprotective or antidepressant-like properties. Taking this into account we investigated antidepressant-like activity in mice and the possible mechanism of action of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-11) – a new xanthone derivative. We demonstrated that HBK-11 produced antidepressant-like effects in the forced swim test and tail suspension test, comparable to that of venlafaxine. The combined treatment with sub-effective doses of HBK-11 and fluoxetine (but not reboxetine or bupropion) significantly reduced the immobility in the forced swim test. Moreover, the antidepressant-like activity of HBK-11 in the aforementioned test was blocked by p-chlorophenylalanine, and significantly reduced by serotonergic 5HT 1A receptor antagonist – WAY-1006335 and 5HT 2A/C receptor antagonist – ritanserin. As none of the above treatments influenced the spontaneous locomotor activity, it can be concluded that HBK-11 mediates its activity through a serotonergic system, and its antidepressant-like effect involves 5HT 1A and 5HT 2A/C receptor activation. Furthermore, at antidepressant-like doses HBK-11 did not cause the mice to display locomotor deficits in rotarod or chimney tests. Considering the pharmacokinetic profile, HBK-11 demonstrated rapid absorption after i.p . administration, high clearance value, short terminal half-life, very high volume of distribution and incomplete bioavailability. The compound studied had good penetration into the brain tissue of mice. Since studied xanthone derivative seems to present interesting, untypical mechanism of antidepressant-like action i.e . 5HT 2A/C receptor activation, it may have a potential in the treatment of depressive disorders, and surely requires further studies. [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]

As part of the presented research, thirteen new aminoalkanol derivatives were designed and obtained by chemical synthesis. In vivo studies (mice, i.p.) showed anticonvulsant activity (MES) of nine compounds, and in the case of one compound (R,S - trans -2-((2-(2,3,5-trimethylphenoxy)ethyl)amino)cyclohexan-1-ol, 4) both anticonvulsant (ED 50 MES = 15.67 mg/kg, TD 50 rotarod = 78.30 mg.kg, PI = 5.00) and analgesic activity (OXA-induced neuropathic pain, active at 15 mg/kg). For selected active compounds additional in vitro studies have been performed, including receptor studies (5-HT 1A), evaluation of antioxidant activity (DPPH assay), metabolism studies as well as safety panel (mutagenicity, safety in relation to the gastrointestinal flora, cytotoxicity towards astrocytes as well as impact on their proliferation and cell cycle). [ABSTRACT FROM AUTHOR]

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-HT 2 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-HT 2A , 5-HT 2B receptors and sodium channels. [ABSTRACT FROM AUTHOR]

Background: Epilepsy frequently coexists with neuropathic pain. Our approach is based on the search for active compounds with multitarget profiles beneficial in terms of potential side effects and on the implementation of screening for potential multidirectional central activity., Methods: Compounds were synthesized by means of chemical synthesis. After antiseizure and neurotoxicity screening in vivo, KM-408 and its enantiomers were chosen for analgesic activity evaluations. Further safety studies included acute toxicity in mice, the effect on normal electrocardiogram and on blood pressure in rats, whole body plethysmography in rats, and in vitro and biochemical assays. Pharmacokinetics has been studied in rats after iv and po administration. Metabolism has been studied in vivo in rat serum and urine. Radioligand binding studies were performed as part of the mechanism of action investigation., Results: Selected results for KM-408: K i sigma = 7.2*10 -8 ; K i 5-HT 1A  = 8.0*10 -7 ; ED 50 MES (mice, ip) = 13.3 mg/kg; formalin test (I phase, mice, ip)-active at 30 mg/kg; SNL (rats, ip)-active at 6 mg/kg; STZ-induced pain (mice, ip)-active at 1 mg/kg (von Frey) and 10 mg/kg (hot plate); hot plate test (mice, ip)-active at 30 mg/kg; ED 50 capsaicin test (mice, ip) = 18.99 mg/kg; tail immersion test (mice)-active at 0.5%; corneal anesthesia (guinea pigs)-active at 0.125%; infiltration anesthesia (guinea pigs)-active at 0.125%., Conclusions: Within the presented study a novel compound, R,S-2-((2-(2-chloro-6-methylphenoxy)ethyl)amino)butan-1-ol hydrochloride (KM-408) with dual antiseizure and analgesic activity has been developed for potential use in neuropathic pain treatment., (© 2022. The Author(s).)

A series of 17 new phenoxyacetamides has been prepared via multistep chemical synthesis as a continuation of the research carried out by our group on di- and tri-substituted phenoxyalkyl and phenoxyacetyl derivatives of amines. The obtained compounds vary in an amide component, for example aminoalkanol or (un)modified amino acid moieties were introduced. The structures of selected products were confirmed by means of crystallographic methods. All 17 compounds were the subject of preliminary screening for potential anticonvulsant activity (MES, 6 Hz and/or scMET tests) and neurotoxicity (rotarod) in mice after intraperitoneal administration, while several active compounds were subsequently examined in additional models ( e.g. MES and rotarod - rats, p.o. or i.p. , hippocampal kindling - rats, i.p. ). Finally, safety studies (cytotoxicity and cell proliferation assays on astrocytes, metabolic stability assessment, mutagenicity evaluation) were performed for several active compounds, including the most promising one ( R -(-)-2-(2,6-dimethylphenoxy)- N -(1-hydroxypropan-2-yl)acetamide, MES ED 50 = 12.00 mg per kg b.w., rats, p.o. ).

Numerous studies have proven that both stimulation and blockade of 5-HT 1A and the blockade of 5-HT 7 receptors might cause the anxiolytic-like effects. Biased agonists selectively activate specific signaling pathways. Therefore, they might offer novel treatment strategies. In this study, we investigated the anxiolytic-like activity, as well as the possible mechanism of action of 1-[(2,5-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-17). In our previous experiments, HBK-17 showed high affinity for 5-HT 1A and 5-HT 7 receptors and antidepressant-like properties. We performed the four plate test and the elevated plus maze test to determine anxiolytic-like activity. Toward a better understanding of the pharmacological properties of HBK-17 we used various functional assays to determine its intrinsic activity at 5-HT 1A , 5-HT 2A , 5-HT 7 , and D 2 receptors and UHPLC-MS/MS method to evaluate its pharmacokinetic profile. We observed the anxiolytic-like activity of HBK-17 in both behavioral tests and the effect was reversed by the pretreatment with WAY-100635, which proves that 5-HT 1A receptor activation was essential for the anxiolytic-like effect. Moreover, the compound moderately antagonized D 2 , weakly 5-HT 7 and very weakly 5-HT 2A receptors. We demonstrated that HBK-17 preferentially activated ß-arrestin signaling after binding to the 5-HT 1A receptor. HBK-17 was rapidly absorbed after intraperitoneal administration and had a half-life of about 150 min. HBK-17 slightly penetrated the peripheral compartment and showed bioavailability of approximately 45%. The unique pharmacological profile of HBK-17 encourages further experiments to understand its mechanism of action fully.

Studies suggest that the blockade of 5-HT 1A , 5-HT 7 , and 5-HT 3 receptor may increase the speed of antidepressant response. 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), dual 5-HT 1A and 5-HT 7 antagonists, showed significant antidepressant- and anxiolytic-like properties in our previous tests in rodents. In this study, we aimed to investigate their antidepressant potential using mouse model of corticosterone-induced depression. We chose sucrose preference test, forced swim test, and elevated plus maze to determine anhedonic-, antidepressant-, and anxiolytic-like activities. We also evaluated the influence of the active compound on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the hippocampus. Moreover, for both compounds, we performed biofunctional (5-HT 3 receptor) and pharmacokinetic studies. We found that HBK-14 and HBK-15 were potent 5-HT 3 receptor antagonists. HBK-14 (2.5 mg/kg) and HBK-15 (1.25 mg/kg) after intravenous (i.v.) and intraperitoneal (i.p.) administration permeated the blood-brain barrier with brain/plasma ratio lower than 1. The bioavailability of studied compounds after i.p. administration was 15% for HBK-14 and 54% for HBK-15. Chronic administration of HBK-15 (1.25 mg/kg) and fluoxetine (10 mg/kg) protected corticosterone-treated mice from anhedonic-, depressive-, and anxiety-like behaviors, as well as decreases in BDNF and NGF levels in the hippocampus. HBK-14 (2.5 mg/kg) counteracted anxiety-like behaviors in corticosterone-treated mice. Single administration of HBK-15 (1.25 mg/kg) and ketamine (1 mg/kg) reversed depression-like behavior and regulated decreased BDNF level in the hippocampus in corticosterone-treated mice. Our results suggest that simultaneous blockade of serotonergic 5-HT 1A , 5-HT 7 , and 5-HT 3 receptors might accelerate antidepressant response.

A series of thirty N-(phenoxy)alkyl or N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(-)-2N-{2-[2-(2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50=12.92 mg/kg b.w. and its rotarod TD50=33.26 mg/kg b.w. The activity dose is also effective in a neurogenic pain model-the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards σ receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Neuropathic pain is a kind of pain related with functional abnormality of neurons. Despite large progress in pharmacotherapy, neuropathic pain is still considered an unmet need. Nowadays, there are few drugs registered for this condition, such as pregabalin, gabapentin, duloxetine, carbamazepine, and lidocaine. Among them, pregabalin, gabapentin and carbamazepine are well known antiepileptic drugs. Among the group of new antiepileptic drugs, which are addressed to 1% of human world population suffering from seizures, it turned out that 30% of the seizures resistant to pharmacotherapy has not enough market to justify the costs of drug development. Therefore, it is already a phenomenon that researchers turn their projects toward a larger market, related with possible similar mechanism. Anticonvulsant mechanism of action is in the first place among primary indications for drugs revealing potential analgesic activity. Therefore, many drug candidates for epilepsy, still in preclinical stage, are being evaluated for activity in neuropathic pain. This review is focusing on antiepileptic drugs, which are evaluated for their analgesic activity in major tests related with neuropathic pain. Relation between structure, mechanism of action and result in tests such as the Chung model (spinal nerve ligation SNL), the Bennett model (chronic constriction injury of sciatic nerve CCI) and other tests are considered. The first examples are carbamazepine, gabapentin, and lacosamide as drugs well established in epilepsy market as well as drug candidates such as valnoctamide, and other valproic acid derivatives, novel biphenyl pyrazole derivatives, etc. Moreover, clinical efficacy related with listed animal models has been discussed.

Gamma-hydroxybutyric acid (GHB) is a naturally occurring substance with function of an inhibitory neurotransmitter in the central nervous system in mammals. GHB can be used as a medicine in narcolepsy (Xyrem) and for general anesthesia (sodium oxybate). It is also a popular drug of abuse, causing coma, addiction and severe withdrawal syndrome, and, therefore, demanding thorough studies on the GHBergic system and expanded research on toxicology of this compound. The aim of this review is to present the proved and some suggested mechanisms of its action from pharmacological point of view, which may help to properly treat intoxication or other pathological states caused by GHB ingestion. Some new GHB derivatives studied for analogous action and their present use are also described.