Jacek Sapa

Synthesis and Evaluation of Antidepressant‐like Activity of Some 4‐Substituted 1‐(2‐methoxyphenyl)Piperazine Derivatives

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 <1 nm (5‐HT1A) and Ki = 34 nm (5‐HT7). Antidepressant‐like activity (tail suspension test) was observed at 2.5 mg/kg b.w. (mice, i.p.), and the effect was stronger than that observed for imipramine (5 mg/kg b.w.). Sedative activity was observed at ED50 (locomotor test, mice, i.p.) = 17.5 mg/kg b.w. and neurotoxicity was observed at TD50 (rotarod, mice, i.p.) = 53.2 mg/kg b.w.

Design, synthesis and pharmacological evaluation of new 1-[3-(4-arylpiperazin-1-yl)-2-hydroxy-propyl]-3,3-diphenylpyrrolidin-2-one derivatives with antiarrhythmic, antihypertensive, and α-adrenolytic activity

A series of novel arylpiperazines bearing a 3,3-diphenylpyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for alpha(1)- and alpha(2)-adrenoceptors (ARs), as well as their antiarrhythmic, and antihypertensive activities. The highest affinity for the alpha(1)-AR was displayed by 1-{3-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (7), which binds with a pK(i)=7.28. The highest affinity for the alpha(2)-AR was shown by 1-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (5), which binds with a pK(i)=6.68. Compound 7 was additionally evaluated in in vitro functional tests for its affinity for alpha(1B)- and alpha(1D)-AR, which gave pA(2) alpha(1B)=6.55 and pA(2) alpha(1D)=7.26. Among the compounds tested, compound 7 also had the highest prophylactic antiarrhythmic activity in adrenaline-induced arrhythmia in anaesthetized rats. Its ED(50) value was 1.1mg/kg (i.v.). The compounds significantly decreased systolic and diastolic pressure in normotensive anaesthetized rats at doses of 2.5-5.0mg/kg (i.v.) and their hypotensive effects lasted for longer than 1h. It was found that the introduction of two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave compounds with affinity for both alpha(1)- and alpha(2)-AR. The substitution of the 2nd position in the phenyl piperazinyl fragment of the molecule was crucial for activity. To determine detailed information concerning the structure-activity relationship, a preliminary molecular modeling study was undertaken.

Synthesis, structure and antiarrhythmic properties evaluation of new basic derivatives of 5,5-diphenylhydantoin.

The synthesis of 1-N and 3-N aminoalkyl derivatives of 5,5-diphenylhydantoin is described. Structural elucidation based on X-ray analysis was performed for two representative compounds 4a and 9b. The effect of tested compounds on the electrocardiogram was examined in vitro in the non-working heart perfusion test and antiarrhythmic activity in the rat coronary artery ligation-reperfusion model. The most active 1-N derivatives 4a and 7b have shown properties of the compounds belonging to class Ia, according to the Vaughan Williams classification. The spatial organisation of the chosen compounds necessary for their pharmacological activity was discussed.

The role of glutamatergic, GABA-ergic, and cholinergic receptors in depression and antidepressant-like effect.

Depression is one of the most common mental disorders and social issue worldwide. Although there are many antidepressants available, the effectiveness of the therapy is still a serious issue. Moreover, there are many limitations of currently used antidepressants, including slow onset of action, numerous side effects, or the fact that many patients do not respond adequately to the treatment. Therefore, scientists are searching for new compounds with different mechanisms of action. Numerous data indicate the important role of glutamatergic, GABA-ergic, and cholinergic receptors in the pathomechanism of major depressive disorder. This review presents the role of glutamatergic, GABA-ergic, and cholinergic receptors in depression and antidepressant-like effect.

Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT1A and 5-HT7 Antagonists in Animal Models

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.

Alpha lipoic acid protects the heart against myocardial post ischemia-reperfusion arrhythmias via KATP channel activation in isolated rat hearts.

The cardiovascular effects of alpha lipoic acid were evaluated in isolated rat hearts exposed to ischemia-reperfusion injury in vitro. Alpha-lipoic acid raised the level of sulfane sulfur playing an important role in the release of hydrogen sulfide. H2S was shown to prevent the post-reperfusion arrhythmias and to protect the cardiomyocytes from death caused by hypoxia. The activation of potassium ATP-sensitive channels (K(ATP) channels) is one of the most important mechanisms of action of hydrogen sulfide in the cardiovascular system. The aim of this study was to investigate whether alpha lipoic acid can prevent the occurrence of post-reperfusion arrhythmias in vitro using a Langendorff model of ischemia-reperfusion in rats affecting the K(ATP) channels. Alpha lipoic acid significantly improved post-reperfusion cardiac function (reducing incidence of arrhythmias), especially in a dose of 10(-7)M. These cardiovascular effects of this compound on the measured parameters were reversed by glibenclamide, a selective K(ATP) blocker. Alpha lipoic acid increased the level of sulfane sulfur in the hearts. This may suggest that the positive effects caused by alpha lipoic acid in the cardiovascular system are not only related to its strong antioxidant activity, and the influence on the activity of such enzymes as aldehyde dehydrogenase 2, as previously suggested, but this compound can affect K(ATP) channels. It is possible that this indirect effect of alpha lipoic acid is connected with changes in the release of sulfane sulfur and hydrogen sulfide.

Antidepressant-like activity of a new piperazine derivative of xanthone in the forced swim test in mice: The involvement of serotonergic system

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

The antidepressant-like activity of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one involves serotonergic 5-HT1A and 5-HT2A/C receptors activation

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 5HT1A receptor antagonist - WAY-1006335 and 5HT2A/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 5HT1A and 5HT2A/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. 5HT2A/C receptor activation, it may have a potential in the treatment of depressive disorders, and surely requires further studies.

Tissue distribution of gold nanoparticles after single intravenous administration in mice

BACKGROUND Nanoparticles (a part of matter which size is less than 100 nm) have numerous potential applications in biomedicine, due to their unique surface, electronic and optical properties. The goal of the present study was to examine the distribution of gold nanoparticles (GNPs) in mice after single intravenous administration. METHODS Spherical GNPs were synthesized by chemical reduction of tetrachloroauric acid with ascorbic acid as a reductant. GNPs were stabilized using polyvinyl alcohol (PVA, m.w. = 67000Da) a substance approved for use in the pharmaceutical industry. The size of colloidal gold particles (diameter equals 25 ± 8 nm) was determined using HR SEM and DLS techniques; ζ potential of GNPs was determined using Malvern Zetasizer Nano ZS and it equals -5.2 ± 5.4 mV. An aqueous dispersion of GNPs was administered to mice in a dose of about 10 cm(3)/kg and 24 h later the amount of gold in different organs was determined using the inductively coupled plasma mass spectrometer (ICP MS). Initial concentration of GNPs equals 29.55 mg/l. RESULTS GNPs after single intravenous administration preferentially accumulated in the liver (12.7% of the applied dose), while the other organs accumulated around 0.1% or less. CONCLUSION Colloidal GNPs of the used size (about 25 ± 8 nm) provide new potential route for direct delivery system to the liver, which may be important e.g., in liver cancer diagnosis.

Antiarrhythmic, hypotensive and α1-adrenolytic properties of new 2-methoxyphenylpiperazine derivatives of xanthone.

The main goal of this study was to assess antiarrhythmic and hypotensive activity of new 2-methoxyphenylpiperazine derivatives of xanthone. In order to better understand mechanism of action of studied compounds, their abilities to antagonize the increase in blood pressure elicited by adrenaline, noradrenaline and methoxamine, as well as the antagonistic properties for α1-adrenoceptors on isolated rat aorta were evaluated. Therapeutic antiarrhythmic activity was investigated in an adrenaline-induced model of arrhythmia. Hypotensive activity in normotensive rats was evaluated after oral administration. Influence on blood vasopressor response and α1-adrenoceptors in rat thoracic aorta was evaluated to determine if the observed cardiovascular effects could be related to α1-adrenolytic properties. Tested compounds produced antiarrhythmic and hypotensive activity. The most active compound was MH-99 - (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride. All studied compounds showed α1-adrenolytic properties in the in vivo and in vitro tests. The results indicate that the new valuable compounds with antiarrhythmic and hypotensive activity might be found in the group of xanthone derivatives. Further pharmacological utility of these compounds should be investigated.