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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-HT1A, α2-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.

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-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (1), R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (2), R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (3), (2E)-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 ED50 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.

5-HT1A and 5-HT7 receptor ligands might have antidepressant-like properties and improve cognitive function. We previously reported significant antidepressant- and anxiolytic-like effects of two dual 5-HT1A and 5-HT7 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-HT1A and 5-HT7 antagonists might have potential in the treatment of depression and possess positive influence on cognitive function.

In vitro mutagenic, antimutagenic, and antioxidant potency evaluation and biotransformation of six novel 4-substituted 1-(2-methoxyphenyl)piperazine derivatives demonstrating antidepressant-like activity were investigated. Mutagenic and antimutagenic properties were assessed using the Ames test; free radical scavenging activity was evaluated with 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay and biotransformation was performed with liver microsomes. It was found that all tested compounds are not mutagenic in bacterial strains TA100 and TA1535 and exhibit antimutagenic effects in the Ames test. Noteworthy, compounds possessing propyl linker between phenoxyl and N-(2-methoxyphenyl)piperazine displayed more pronounced antimutagenic properties than derivatives with ethoxyethyl linker. Additionally, compounds 2 and 6 in vitro biotransformation showed that primarily their hydroxylated or O-dealkylated metabolites are formed. Some of the compounds exhibited intrinsic clearance values lower than those reported previously for antidepressant imipramine. To sum up, the results of the present study might represent a valuable step in designing and planning future studies with piperazine derivatives.

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, 6 Hz 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.

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).

Summary Reactive oxygen species (ROS) are critically involved in the action of anticancer agents. In this study, we investigated the role of ROS in the anticancer mechanism of new aminoalkanol derivatives of xanthone. Most xanthones used in the study displayed significant pro-oxidant effects similar to those of gambogic acid, one of the most active anticancer xanthones. The pro-oxidant activity of our xanthones was shown both directly (by determination of ROS induction, effects on the levels of intracellular antioxidants, and expression of antioxidant enzymes) and indirectly by demonstrating that the overexpression of manganese superoxide dismutase decreases ROS-mediated cell senescence. We also observed that mitochondrial dysfunction and cellular apoptosis enhancement correlated with xanthone-induced oxidative stress. Finally, we showed that the use of the antioxidant N-acetyl-L-cysteine partly reversed these effects of aminoalkanol xanthones. Our results demonstrated that novel aminoalkanol xanthones mediated their anticancer activity primarily through ROS elevation and enhanced oxidative stress, which led to mitochondrial cell death stimulation; this mechanism was similar to the activity of gambogic acid.

Most antidepressants lower seizure threshold, which might be due to the modulation of serotonergic neurotransmission. Here, we investigated the effects of two 5-HT

Studies suggest that the blockade of 5-HT1A, 5-HT7, and 5-HT3 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-HT1A and 5-HT7 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-HT3 receptor) and pharmacokinetic studies. We found that HBK-14 and HBK-15 were potent 5-HT3 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-HT1A, 5-HT7, and 5-HT3 receptors might accelerate antidepressant response.

A series of new xanthone derivatives have been synthesized and evaluated for their anticonvulsant properties in the maximal electroshock (MES), subcutaneous metrazole (ScMet) tests as well as for neurotoxicity in the rotarod (TOX) in mice, i.p. and rats, p.o. Compound 9: R,S-2-{2-[(1-hydroxybutan-2-yl]amino)ethoxy}-9H-xanthen-9-one and compound 12: R,S-2-{3-[(1-hydroxybutan-2-yl)amino]propoxy}-9H-xanthen-9-one exerted activity in rats, p.o. 2 and 4 h after administration, respectively. Therefore, metabolic stability of the compounds was evaluated with use of rats microsomes, resulting in half-life t1/2 136 and 108 min, respectively, indicating that either the metabolites are very active, or the parent compounds exert other ADME properties other than metabolism which influence the late onset of activity. This article is protected by copyright. All rights reserved.

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.

A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH

A series of (E)-α-methylcinnamyl derivatives of selected aminoalkanols was synthetized and evaluated for activity in central nervous system. All compounds were tested as anticonvulsants and one additionally in antidepressant- and anxiolytic-like assays. The compounds possessed pharmacophoric elements regarded as beneficial for anticonvulsant activity: hydrophobic unit and two hydrogen bonds donor/acceptor features. The compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scPTZ) induced seizures as well as neurotoxicity assessments. Eight of the tested substances showed protection in MES test at the dose of 100 mg/kg. The derivative of 2-aminopropan-1-ol was also tested in 6-Hz test in mice i.p. and showed anticonvulsant activity but at the same time the neurotoxicity was noted. The derivative of 2-amino-1-phenylethanol which possessed additional hydrophobic unit in aminoalkanol moiety was tested in other in vivo assays to evaluate antidepressant- and anxiolytic-like activity. The compound proved beneficial properties especially as anxiolytic agent remaining active in four-plate test in mice at the dose of 2.5 mg/kg (i.p.). In vitro biotransformation studies of 2-amino-1-phenylethanol derivative carried out in mouse liver microsomal assay indicated two main metabolites as a result of aliphatic and aromatic hydroxylation or aliphatic carbonylation. To identify possible mechanism of action, we evaluated serotonin receptors (5-HT1A, 5-HT6 and 5-HT7) binding affinities of the compounds but none of them proved to bind to any of tested receptors.

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-HT1A receptor agonist, and 5-HT2A receptor antagonist, with high affinity toward 5-HT7 receptors, showing antidepressant- and anxiolytic-like properties. Moreover, 5-HT1A 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-HT1A receptors activation. Furthermore, the compounds are 5-HT1A and weak 5-HT3 receptors antagonists, and some of them 5-HT2A 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.

Xanthone derivatives possess many biological properties, including neuroprotective, antioxidant or antidepressant-like. In this study we aimed to investigate antidepressant- and anxiolytic-like properties of a new xanthone derivative - 6-methoxy-4-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-7), as well as its possible mechanism of action, and the influence on cognitive and motor function. HBK-7 in our earlier studies showed high affinity for serotonergic 5-HT1A receptor. We determined the affinity of HBK-7 for CNS receptors and transporters using radioligand assays and examined its intrinsic activity towards 5-HT1A receptor. We evaluated antidepressant- and anxiolytic-like activity of HBK-7 in the mouse forced swim test, and four-plate test, respectively. We examined the influence on locomotor activity in mice to determine if the effect observed in the forced swim test was specific. We used step-through passive avoidance and rotarod tests to evaluate the influence of HBK-7 on cognitive and motor function, respectively. HBK-7 showed moderate affinity for dopaminergic D2 receptor and very low for serotonergic 5-HT2A, adrenergic α2 receptors, as well as serotonin transporter. Functional studies revealed that HBK-7 was a 5-HT1A receptor antagonist. HBK-7 (10mg/kg) decreased immobility time in the forced swim test. Combined treatment with sub-effective doses of HBK-7 and fluoxetine reduced immobility of mice in the forced swim test. Pretreatment with p-chlorophenylalanine and WAY-100,635 antagonized the antidepressant-like effect of HBK-7. Neither of the treatments influenced locomotor activity of mice. HBK-7 at antidepressant-like dose did not impair memory or motor coordination in mice. We demonstrated that HBK-7 was a 5-HT1A receptor antagonist with potent, comparable to mianserin, antidepressant-like activity. HBK-7 mediated its effect through serotonergic system and its antidepressant-like action required the activation of 5-HT1A receptors. At active dose it did not influence cognitive and motor function. Since 5-HT1A receptor antagonists may accelerate the occurrence of antidepressant effect, our findings highlight their potential as future antidepressants.

A group of trans - and cis -2-(2,6-dimethylphenoxy)- N -(2-hydroxycyclohexyl)acetamides ( 1 – 7 ) and -ethylamines ( 8 – 9 ) have been synthesized and investigated for their anticonvulsant activity. One of them, racemic trans -2-(2,6-dimethylphenoxy)- N -(2-hydroxycyclohexyl)acetamide proved to be the most effective in MES (mice, ip), exhibiting ED 50 = 42.97 mg/kg b.w. and TD 50 = 105.67 mg/kg b.w. It also proved protection in focal seizures (electric kindling, rats, ip) and it raises seizure threshold. The mechanism of action is inhibition of voltage-gated sodium currents and enhancement of GABA effect. Safety pharmacology assay on threshold tonic extension revealed no lowering of the seizure threshold.

A series of new (phenoxyethyl)aminoalkanol derivatives were synthesized and evaluated for their anticonvulsant activity. The most promising compound seemed to be (R,S)-1N-[(2,6-dimethyl)phenoxyethyl]amino-2-butanol, which displayed anti-MES activity (in mice, i.p.) with protective index (TD50/ED50) of 5.712, corresponding to that of phenytoin (6.6), carbamazepine (4.9) and valproate (1.7). The lipophilicity of compounds 1–17 exhibiting anticonvulsant activity was investigated. Their lipophilicities (RM0) were determined using reversed-phase thin-layer chromatography (RP-TLC) with a mixture of acetone and water as mobile phases. The partition coefficients of 1–17 (logP) were also calculated using two computer programs (Pallas and ALOGPS) and compared with RM0. The relationship between anticonvulsant activity and lipophilicity of the tested substances was estimated. Copyright © 2010 John Wiley & Sons, Ltd.

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 RM0, 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 ED50 values of 86.6, 60.9, and 109.6 mg/kg in the MES, 6-Hz, and scPTZ tests, respectively. For compound 3, the ED50 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 A--from the phenyl ring to the hydroxyl group in the amide moiety, 5.729 A--from the phenyl ring to the amide group, and 3.112 A--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).

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-chlorophertylalanine, and significantly reduced by serotonergic $5-HT_{1A}$ receptor antagunist - WAY-1006335 and $5-HT_{2A/C}$ receptor antagonist - ritanserin. As none of the above treatments influenced the spontaneous locomotor activity, if can be concluded that HBK-11 mediates its activity through a serotonergic system, and its antidepressant like effect involves $5-HT_{1A}$ and $5-HT_{2A/C}$ receptor activation. Furthermore, at antidepressant like doses HBK-11 did not cause the mice to display locomotor deficits in rotarod or chimney rests. 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 bioavailabilily. 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. $5-HT_{2A/C}$ receptor activation, it may have a potential in the treatment of depressive disorders, and surely requires further studies.

A series of new N-(2,5-dimethylphenoxy)- and N-(2,3,5-trimethylphenoxy)alkylaminoalkanols [I-XVII] was synthesized and evaluated for anticonvulsant activity. Pharmacological tests included maximal electroshock (MES) and subcutaneous pentetrazole seizure threshold (scMet) assays as well as neurotoxicity (TOX) evaluation in mice after intraperitoneal (i.p.) administration and/or in rats after oral (p.o.) administration. The most active compound was R-2N-[(2,3,5-trimethylphenoxy)ethyl]aminobutan-1-ol, which exhibited 100% activity in MES at the dose of 30 mg/kg body weight (mice, i.p.) and 75% activity in MES at 30 mg/kg b.w. (rats, p.o.) without neurotoxicity at the active doses.

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.

The studied compound: 3-chloro-5-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-9H-xanthen-9-one dihydrochloride (HBK-6) is a new xanthone derivative. In this study we investigated its antidepressant-like properties and possible mechanism of action.Antidepressant-like activity was evaluated in the forced swim test (FST) in mice. The influence on locomotor activity in mice was analyzed to determine whether the observed in FST effect is specific. Rotarod test was used to determine neurotoxic properties.HBK-6 reduced immobility time in mice in FST at the doses 5 and 10mg/kg, whereas fluoxetine (FX) at 15 mg/kg, reboxetine (RX) at 10mg/kg and bupropion (BPR) at 5mg/kg. Joint administration of sub-effective doses of HBK-6 and FX, but not RX or BPR, reduced immobility in mice in FST. HBK-6 at the dose 5mg/kg did not show activity in FST after pretreatment with p-chlorophenylalanine. The studied xanthone derivative at the doses 5 and 10mg/kg did not impair motor coordination in mice.We demonstrated that HBK-6 has a potent antidepressant-like activity in FST, stronger than that of FX and RX, and seems to mediate its effect through serotonergic system. Moreover, at antidepressant-like doses it does not show neurotoxic properties. Given the promising results, HBK-6 may have potential in the treatment of depression, but this needs extended studies.

A series of new derivatives of N-(2-methoxyphenyl)piperazine have been synthesized for their affinity toward serotonergic receptors and for their potential antidepressant-like activity. They have been evaluated toward receptors 5-HT1A , 5-HT6 , and 5-HT7 , as well as in vivo in the tail suspension, locomotor activity, and motor co-ordination tests. All the tested compounds proved very good affinities toward 5-HT1A and 5-HT7 receptors. The most promising compound was 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride, exhibiting affinity toward receptors Ki

Twenty four new N-[(dimethylphenoxy)alkyl]aminoalkanols have been synthesized and evaluated for anticonvulsant activity in a series of in vivo tests: the maximum electroshock (MES), 6 Hz, and subcutaneous metrazole (ScMet). The compounds were also evaluated for possible neurotoxicity in the rotarod test. The majority of the achieved compounds exhibit quantified anticonvulsant activity. The most active compound 4: R-(−)-2N-[(2,6-dimethylphenoxy)ethyl]aminopropan-1-ol is active in MES with ED50 = 5.34 (male mice, ip), 22.28 (female mice, ip), 51.19 (male mice, po), 7.43 (rats, ip), and 28.60 (rats, po). Thermal analysis proved that its hydrochloride (4a) can exist in polymorphic forms. The compound binds to σ, 5-HT1A, and α2 receptors as well as 5-HT transporter and it does not exhibit mutagenic properties.

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.

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 100 mg/kg. Additionally, one was effective at the dose of 30 mg/kg. Five substances were active at the dose of 300 mg/kg or at the dose of 100 mg/kg in the minority of the tested mice. The most promising compound revealed ED(50) value of 47.57 mg/kg in MES (mice, ip, 1h after administration) and at the same time its TD(50) was evaluated as above 400 mg/kg. Those values gave PI (calculated as TD(50)/ED(50)) of more than 8.41. Three other synthesized xanthone derivatives also proved to act as anticonvulsants and showed ED(50) values in MES test (mice, ip) ranged 80-110 mg/kg. Results were quite encouraging and suggested that in the group of xanthone derivatives new potential anticonvulsants might be found.

A variety of appropriate [4-(benzyloxy) benzoyl]- and [4-(benzyloxy) benzyl] aminoalkanol derivatives [I-XVII] was synthesized and evaluated for anticonvulsant activity using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (ScMet) tests in mice and rats. Neurotoxicity (TOX) was determined by the rotorod test. The most active compounds in the MES test in mice were the appropriate 4-(benzyloxy) benzyl derivatives of (R,S)- and S-(+)-2-amino-1-butanol [XI, XIII], 3-[4-(benzyloxy) benzyl] amino-3-methyl-1-butanol [XV], and S-(+)-2-[4-(benzyloxy) benzyl] amino-3-methyl-1-butanol [XVI]--all exhibiting 100% anti-MES protection (at 30 mg/kg, mice, i.p.) and non-toxic in the active doses. 4-[4-(Benzyloxy) benzyl] amino-1-butanol [X] exhibited activity in both MES and ScMet (100 mg/kg, mice, i.p., 100% anticonvulsant protection, 0.5 h and 4 h after administration, respectively).

A series of aroxyacetamides and aroxyethylamines were prepared and evaluated for anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure threshold (ScMet) assays and for neurotoxicity (TOX). Most of them exhibited anticonvulsant activity in the MES screen (mice, i.p.) in the doses up to 300 mg/kg b.w. The most active compound was XVI, which given in the dose 100 mg/kg b.w. produced 100% anticonvulsant protection after 0.5 h without neurotoxicity. The most promising compound in the VIa phase (rats, p.o.) was VIII, which produced higher anticonvulsant protection (to 75% at 0.5 h).