Novel xanthone derivatives as potent sirtuin 2 inhibitors.

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.

Anticonvulsant and analgesic in neuropathic pain activity in a group of new aminoalkanol derivatives.

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 (ED50 MES = 15.67 mg/kg, TD50 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-HT1A), 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).

Four N-(E)-cinnamoyl (cinnamamide) derivatives of aminoalkanols with promising anticonvulsant and analgesic activity.

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.

Design, synthesis and evaluation of activity and pharmacokinetic profile of new derivatives of xanthone and piperazine in the central nervous system.

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.

Beneficial effects of non-quinazoline α1-adrenolytics on hypertension and altered metabolism in fructose-fed rats. A comparison with prazosin.

BACKGROUND AND AIMS: Metabolic syndrome associated with insulin resistance and hypertension is often caused by excessive fructose consumption. Treatment of hypertension in patients with metabolic syndrome is a difficult task as many antihypertensive drugs have adverse effects on the metabolic profile. We investigated if MH-76 and MH-79, non-quinazoline α1-adrenoceptor antagonists with an additional ability to stimulate NO/cGMP/K+ pathway, ameliorates metabolic syndrome in fructose-fed rats. As reference compound prazosin was used. METHODS AND RESULTS: Male rats were divided into 5 groups (n = 8) and studied for 18 weeks: group control: standard diet and drinking water; group Fructose: high-fructose diet (20% fructose in drinking water); groups Fructose + MH-76, Fructose + MH-79, Fructose + prazosin: high-fructose diet with subsequent MH-76, MH-79 (5 mg/kg/day ip) or prazosin (0.2 mg/kg/day ip) treatment 12 weeks later. In addition to their antihypertensive effect, the studied compounds reversed endothelial dysfunction, decreased hyperglycemia and hypertriglyceridemia, as well as prevented abdominal adiposity. Moreover, MH-76 reduced insulin resistance and decreased TNF-α concentration and lipid peroxidation in adipose tissue. Prazosin treatment exerted an antihypertensive effect, reduced hyperglycemia but did not improve endothelial dysfunction, insulin resistance, and abdominal adiposity. The lower efficacy of prazosin may be the result of its short half-time and the lack of described pleiotropic effects. CONCLUSIONS: α1-adrenoceptor blockade, endothelial protection, TNF-α suppressing and antioxidant activity together with favorable pharmacokinetic parameters determines high efficacy of MH-76, leading to the effective improvement of hemodynamic and metabolic disturbances in metabolic syndrome. The use of non-quinazoline, multiple-targeted α1-blockers may be an interesting option for treatment of hypertension with metabolic complications.

Contribution of reactive oxygen species to the anticancer activity of aminoalkanol derivatives of xanthone.

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.

Synthesis and activity of di- or trisubstituted N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives on the central nervous system.

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).

Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3.

A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3 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-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5) (ED50 MES=42.56, ED50 scPTZ=58.38, ED50 6-Hz 44mA=42.27mg/kg tested in mice after intraperitoneal (i.p.) administration); R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (6) (ED50 MES=53.76, ED50 scPTZ=90.31, ED50 6-Hz 44mA=92.86mg/kg mice, i.p.); and R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (11) (ED50 MES=55.58, ED50 scPTZ=102.15, ED50 6-Hz 44mA=51.27mg/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.

HBK-14 and HBK-15 with antidepressant-like and/or memory-enhancing properties increase serotonin levels in the hippocampus after chronic treatment in mice.

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.

Synthesis and activity of newly designed aroxyalkyl or aroxyethoxyethyl derivatives of piperazine on the cardiovascular and the central nervous systems.

In the search for new hypotensive agents some new aroxyalkyl or aroxyethoxyethyl derivatives of piperazine have been synthesized and evaluated for their pharmacological properties. Pharmacological tests included receptor binding assays toward adrenergic receptors α1, α2 and ß1, additionally 5-HT1A, functional bioassay and in vivo evaluation of hypotensive activity as well as antidepressant-like potential. All the tested compounds exhibited α1-antagonistic properties, three of them possessed also hypotensive activity in rats. The most promising compound 3 1-[4-(2,6-dimethylphenoxy)butyl]-4-(2-methoxyphenyl)piperazine hydrochloride was a selective α1 receptor antagonist (Ki=23.5±1.3, α1/α2=15.77, pKB=8.538±0.109). It was active in all tested doses in vivo (1, 0.5, and 0.1mg/kg) and it reduced blood pressure by 10-13% at the dose of 1mg/kg (rats, i.v.). Compound 5 1-[2-(2,3-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine dihydrochloride exhibited the lowest dose for antidepressant-like activity 5mg/kgb.w. (mice, i.p.) without influence on spontaneous activity (mice, i.p.).

In vitro mutagenic, antimutagenic, and antioxidant activities evaluation and biotransformation of some bioactive 4-substituted 1-(2-methoxyphenyl)piperazine derivatives.

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.

PRELIMINARY EVALUATION OF CENTRAL NERVOUS SYSTEM ACTIVITY OF (E)-N-2-METHYL-3-PHENYLPROP-2-ENYL ((E)-N- α-METHYLCINNAMYL) DERIVATIVES OF SELECTED AMINOALKANOLS.

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.

N-[(2,6-Dimethylphenoxy)alkyl]aminoalkanols-their physicochemical and anticonvulsant properties.

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.

Synthesis and evaluation of anticonvulsant activity of N-(2,5-dimethylphenoxy)- and N-[(2,3,5-trimethylphenoxy)alkyl]aminoalkanols.

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.

Simultaneous LC/ESI-MS separation method for the enantioseparation of some new anticonvulsant drugs.

A sensitive and specific method for the simultaneous determination of the enantiomeric purity of 2,6-dimethylphenoxyacetyl derivatives as trans or cis racemic and enantiomeric forms with 2- or 4-aminocyclohexanol moiety (1, 2, 3, 6) and their amine analogs (8, 9) was developed. The compounds studied are known for their anticonvulsant activity and the most interesting pharmacological results were those for (±)-trans-2-(2,6-dimethylphenoxy)-N-(2-hydroxycyclohexyl)acetamide (1) as well as (±)-trans-2-[(2,6-dimethylphenoxy)ethyl]aminocyclohexanol (8). The analytical method for determining the enantiomeric purity of the compounds studied is based on direct separation of the analytes using a chiral stationary phase (Chiralpak AS column). The mass spectrometric analysis was done on a coupled liquid chromatograph-mass spectrometer system with an electrospray ionization source (LC/ESI-MS). For the compounds 1, 8, and 9, the method allows an excellent separation of enantiomers, with a resolution higher than 3.2, and a tailing factor of less than 1.67 with a final enantiomer purity better than 97.5%.

The nitric oxide/soluble cyclic guanylase/cyclic guanosine monophosphate pathway is involved in the cardiovascular effects of a novel α1- and ß-adrenoceptor antagonist.

The compound MH-78 ((+/-)-1-(2,6-dimethylphenoxy)-3-{4-[2-(2-methoxyphenoxy)ethyl]-piperazin-1-yl}propan-2-ol dihydrochloride) contains structural elements that are typical for α1- and ß-blockers. This study aimed to investigate the hypotensive activity as well as the in vitro and in vivo cardiovascular effects of a novel α1- and ß-adrenoceptor antagonist (MH-78) and compare it with carvedilol and urapidil. The procedures were performed on aortic rings of normotensive anesthetized rats. MH-78 decreased the blood pressure and heart rate after intravenous and oral administration. MH-78 possesses both α1- and ß-adrenoceptor blocking activity, which was confirmed in the in vivo study. In biofunctional assays, MH-78 displayed vasorelaxant activity due to α1-adrenoceptor antagonism and calcium channel blocking properties. Moreover, in endothelium-intact aortic rings, pretreatment with Nω-nitro-L-arginine methyl ester (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the MH-78-induced vasorelaxation to a level that is characteristic for MH-78 affinity to α1-adrenoceptors. Our results demonstrated that MH-78 possesses α1- and ß-adrenoceptor blocking properties and induces potent hypotensive and vasorelaxant effects. Moreover, it relaxes vascular smooth muscle not only due to α1-adrenoceptor blocking activity, but also via the endothelium-dependent nitric oxide/soluble guanylyl cyclase/cyclic guanosine monophosphate signalling pathway.

Anticonvulsant evaluation of aminoalkanol derivatives of 2- and 4-methylxanthone.

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.

Promising anticonvulsant and/or analgesic compounds among 5-chloro-2- or 5-chloro-4-methyl derivatives of xanthone coupled to aminoalkanol moieties-Design, synthesis and pharmacological evaluation.

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.

KM-408, a novel phenoxyalkyl derivative as a potential anticonvulsant and analgesic compound for the treatment of neuropathic pain.

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: Ki sigma = 7.2*10-8; Ki 5-HT1A = 8.0*10-7; ED50 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; ED50 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.

Influence of protonation on the geometry of 2-{[(2,6-dimethylphenoxy)ethyl]amino}-1-phenylethan-1-ol: crystal structures of the free base and of its chloride and 3-hydroxybenzoate salt forms.

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.