Sleep Disturbances and Health Consequences Induced by the Specificity of Nurses' Work.

INTRODUCTION: Nursing staff working in a shift or night system are exposed to sleep disorders, which has a direct impact on the emergence of dangerous health consequences for them. Melatonin secretion is abnormal at night and the circadian rhythm is disturbed. The aim of the study was to assess the occurrence of sleep disorders and their consequences for the body in a group of representative nursing staff working in a shift and night system. PARTICIPANTS: The study was conducted among 126 nurses who are generally healthy, employed in health care facilities in the Malopolskie voivodship. METHODS: The Athens Insomnia Scale consisting of 8 test items was used to obtain research material: falling asleep, waking up at night, waking up in the morning, total sleep time, sleep quality, well-being the next day, mental and physical fitness the next day, and sleepiness during the next day. As well as an original questionnaire. RESULTS: The research showed significant negative consequences of shift work on the health of health-care workers. The subjects noticed symptoms related to the nervous system, such as increased nervous tension 53%, lack of patience in 62% of all respondents. As many as 85% pointed to the negative impact of shift work on their family life, 82% of all respondents on social life and 56% of all respondents on sex life. The other variables were not confirmed. CONCLUSIONS: Symptoms of insomnia are common among night-work nurses.

Oligodendrocyte morphometry and expression of myelin - Related mRNA in ventral prefrontal white matter in major depressive disorder.

White matter disturbance in the ventral prefrontal cortex (vPFC) in major depressive disorder (MDD) has been noted with diffusion tensor imaging (DTI). However, the cellular and molecular pathology of prefrontal white matter in MDD and potential influence of antidepressant medications is not fully understood. Oligodendrocyte morphometry and myelin-related mRNA and protein expression was examined in the white matter of the vPFC in MDD. Sections of deep and gyral white matter from the vPFC were collected from 20 subjects with MDD and 16 control subjects. Density and size of CNPase-immunoreactive (-IR) oligodendrocytes were estimated using 3-dimensional cell counting. While neither density nor soma size of oligodendrocytes was significantly affected in deep white matter, soma size was significantly decreased in the gyral white matter in MDD. In rhesus monkeys treated chronically with fluoxetine there was no significant effect on oligodendrocyte morphometry. Using quantitative RT-PCR to measure oligodendrocyte-related mRNA for CNPase, PLP1, MBP, MOG, MOBP, Olig1 and Olig2, in MDD there was a significantly reduced expression of PLP1 mRNA (which positively correlated with smaller sizes) and increased expression of mRNA for CNPase, OLIG1 and MOG. The expression of CNPase protein was significantly decreased in MDD. Altered expression of four myelin genes and CNPase protein suggests a mechanism for the degeneration of cortical axons and dysfunctional maturation of oligodendrocytes in MDD. The change in oligodendrocyte morphology in gyral white matter may parallel altered axonal integrity as revealed by DTI.

Coverage of blood vessels by astrocytic endfeet is reduced in major depressive disorder.

BACKGROUND: Depression and cerebrovascular disease influence each other, according to clinical studies. Despite this evidence, no studies have investigated the relationship between major depressive disorder (MDD) and cerebrovascular disease at the cellular level. Astrocytic processes are a crucial interface between blood vessels and neurons, and astrocyte density is reduced in MDD. This study investigated the coverage of vessels by astrocyte endfeet in the prefrontal cortex in MDD. METHODS: Thirteen pairs of MDD and nonpsychiatric control subjects were used for double immunofluorescent staining and confocal image analysis. Frozen sections of gray matter from orbitofrontal area 47 and white matter from the ventromedial prefrontal cortex were examined. Astrocytic processes (labeled with antibodies for aquaporin-4 (AQP4) or glial fibrillary acidic protein were co-localized with blood vessels (labeled with an antibody to collagen IV) to measure the coverage of vessel walls by astrocyte processes. RESULTS: The coverage of blood vessels by endfeet of AQP4-immunoreactive (IR) astrocytes was significantly reduced by 50% in subjects with MDD as compared with control subjects [analysis of covariance: F(1,23) = 5.161, p = .033]. This difference was detected in orbitofrontal gray matter but not in white matter. Conversely, the coverage of vessels by glial fibrillary acidic protein-IR processes did not significantly differ between the groups. CONCLUSIONS: A significant reduction in the coverage of gray matter vessels by AQP4-IR astrocyte processes in MDD suggests alterations in AQP4 functions such as regulation of water homeostasis, blood flow, glucose transport and metabolism, the blood-brain barrier, glutamate turnover, and synaptic plasticity.

Antiarrhythmic properties of phenylpiperazine derivatives of phenytoin with α1-adrenoceptor affinities.

An association between α(1)-adrenoceptor affinities, hERG K(+)-antagonistic properties and antiarrhythmic activities for a series of phenylpiperazine derivatives of hydantoin (2a-21a) was investigated. New compounds were synthesized and tested for their affinity for α(1)-adrenoceptors in radioligand binding assay using [(3)H]-prazosin as a selective radioligand. Antiarrhythmic activities in adrenaline- and barium chloride-induced arrhythmia models, an influence of the phenylpiperazine derivatives on the ECG-components and blood pressure were tested in vivo in normotensive rats. The hERG K(+)-antagonistic properties of the most potent antiarrhythmic agents were investigated in silico by the use of program QikProp. The highest α(1)-adrenoceptor affinity (K(i)=4.7 nM) and the strongest antiarrhythmic activity in adrenaline induced arrhythmia (ED(50)=0.1 mg/kg) was found for 1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione hydrochloride (19a). The results indicated a significant correlation between α(1)-AR affinities (pK(i)) and antiarrhythmic activity (ED(50)) in adrenaline model (R(2)=0.92, p <0.005). Influence of the examined phenylpiperazine hydantoin derivatives on hERG K(+) channel, predicted by means of in silico methods, suggested their hERG K(+)-blocking properties.

Dose-dependent effects of neonatal SSRI exposure on adult behavior in the rat.

Neonatal exposure to antidepressants produces lasting impairments in male sexual behavior. Although perturbation of the serotonin system during neonatal life has been implicated in the long-term behavioral effects of neonatal antidepressant exposure, dose-response studies were necessary to confirm that inhibition of the serotonin transporter during the neonatal period is sufficient to produce impairments in sexual behavior. Therefore, the present study examined the dose-response effects of neonatal citalopram exposure on sexual behavior. In addition, the effects of exposure on anxiety-related behavior were examined since alterations in this behavioral measure could affect sexual behavior. Male Long-Evans rats were injected subcutaneously with citalopram (CTM) in one of three doses (5, 10 or 20mg/kg/d), or saline (SAL) in a volume of 0.1 ml twice daily (07:00 and 14:00 h) from PD8 to PD21. The rats were tested as adults (>PD90) for anxiety-like behavior and exploration in the elevated plus maze test and sexual behavior. Neonatal citalopram exposure produced persistent reductions in male sexual behavior characterized by significant dose-dependent reductions in the percentage of male rats displaying mounting as well as dose-dependent reductions in the number of mounts and mount latency. Neonatal citalopram exposure also produced significant dose-dependent linear trends for reductions in intromission and ejaculation behavior. However, neonatal SSRI exposure was not found to produce any effects on exploration or anxiety-like behavior in the elevated plus maze test. The present findings support the hypothesis that inhibition of the serotonin transporter during neonatal life by an SSRI is directly responsible for the long-term effects on male sexual behavior.

Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression.

Accumulating evidence suggests dysfunction of the gamma-aminobutyric acid (GABA) system in major depressive disorder (MDD). Neuroimaging studies consistently report reductions of cortical GABA in depressed patients. Our post-mortem analyses demonstrate a reduction in the density and size of GABAergic interneurons in the dorsolateral prefrontal cortex (DLPFC) in MDD. The goal of this study was to test whether the level of glutamic acid decarboxylase (GAD), the GABA synthesizing enzyme, will also be reduced in the same cortical region in MDD. Levels of GAD-65 and GAD-67 proteins were investigated by Western blotting in samples from the DLPFC (BA 9) in 13 medication-free subjects with MDD, and 13 psychiatrically healthy controls. The overall amount of GAD-67 was significantly reduced (-34%) in depressed subjects compared to matched controls. Since recent neuroimaging studies have demonstrated that antidepressants modulate GABA levels, additional experiments were performed to examine the levels of GAD in eight depressed subjects treated with antidepressant medications. Levels of GAD-67 were unchanged in these depressed subjects compared to their respective controls (n=8). The overall amounts of GAD-65 were similar in depressed subjects compared to matched controls, regardless of antidepressant medication. Reduced levels of GAD-67, which is localized to somata of GABA neurons, further support our observation of a decreased density of GABAergic neurons in the PFC in depression. It is likely that a decrease in GAD-67 accounts for the reduction in GABA levels revealed by neuroimaging studies. Moreover, our data support previous neuroimaging observations that antidepressant medication normalizes GABA deficits in depression.

Reduced density of calbindin immunoreactive GABAergic neurons in the occipital cortex in major depression: relevance to neuroimaging studies.

BACKGROUND: Several lines of evidence suggest dysfunction of the gamma-aminobutyric acid (GABA)ergic system in major depressive disorder. Neuroimaging studies report reduced levels of GABA in the dorsolateral prefrontal and occipital cortex of depressed patients. Our previous postmortem study revealed a reduction in the density and size of calbindin-immunoreactive (CB-IR) GABAergic neurons in the prefrontal cortex in major depressive disorder. The goal of this study was to test whether the changes in CB-IR neurons can also be detected in the occipital cortex, where neuroimaging studies report a prominent GABA decrease. METHODS: A three-dimensional cell counting probe was used to assess the cell-packing density and size of CB-IR neurons in layer II of the occipital cortex in 10 major depressive disorder subjects and 10 psychiatrically healthy control subjects. RESULTS: The density of CB-IR neurons was significantly decreased by 28% in major depressive disorder subjects compared with the control group. The size of CB-IR neurons was unchanged in major depressive disorder subjects when compared with control subjects. CONCLUSIONS: The reduction in the density of CB-IR GABAergic neurons in the occipital cortex in depression is similar to that observed previously in the prefrontal cortex. Deficit in cortical GABAergic interneurons may contribute to the low GABA levels detected in neuroimaging studies in major depressive disorder patients.

Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression.

Compelling evidence suggests that major depression is associated with dysfunction of the brain glutamatergic transmission, and that the glutamatergic N-methyl-d-aspartate (NMDA) receptor plays a role in antidepressant activity. Recent post-mortem studies demonstrate that depression is associated with altered concentrations of proteins associated with NMDA receptor signalling in the brain. The present study investigated glutamate signalling proteins in the amygdala from depressed subjects, given strong evidence for amygdala pathology in depression. Lateral amygdala samples were obtained from 13-14 pairs of age- sex-, and post-mortem-interval-matched depressed and psychiatrically healthy control subjects. Concentrations of NR1 and NR2A subunits of the NMDA receptor, as well as NMDA receptor-associated proteins such as post-synaptic density protein-95 (PSD-95) and neuronal nitric oxide synthase (nNOS) were measured by Western immunoblotting. Additionally, levels of enzymes involved in glutamate metabolism, including glutamine synthetase and glutamic acid decarboxylase (GAD-67), were measured in the same amygdala samples. NR2A protein levels were markedly and significantly elevated (+115%, p=0.03) in depressed subjects compared to controls. Interestingly, PSD-95 levels were also highly elevated (+128%, p=0.01) in the same depressed subjects relative to controls. Amounts of NR1, nNOS, glutamine synthetase, and GAD-67 were unchanged. Increased levels of NR2A and PSD-95 suggest that glutamate signalling at the NMDA receptor in the amygdala is disrupted in depression.

Synthesis, alpha 1-adrenoceptor antagonist activity, and SAR study of novel arylpiperazine derivatives of phenytoin.

In the search for new antiarrhythmic agents, some active 2-methoxyphenylpiperazine derivatives of phenytoin were obtained as a chemical modification of compound AZ-99 (3-ethyl-1-[2-hydroxy-3-(4-phenylpiperazin-1-yl)-propyl]-2,4-dioxo-5,5-diphenylimidazolidine). These compounds possessed structural properties similar to those of alpha(1)-adrenoceptor antagonists. In the present study, the affinities of the 2-methoxyphenylpiperazine derivatives (1a-3a) for alpha(1)- and alpha(2)-adrenoceptors were evaluated using radioligand ([(3)H]prazosin, [(3)H]clonidine) binding assays. In the next step, a new series of phenylpiperazine derivatives of phenytoin (4a-16a) containing 2-methoxyphenyl-, 2-ethoxyphenyl-, 2-pyridyl- or 2-furoylpiperazine moiety, as well as, various ester or alkyl substituents at 3-position of hydantoin ring were synthesized. The newly synthesized compounds were tested for their affinity to alpha(1)- and alpha(2)-adrenoceptors. They have shown affinities for alpha(1)-adrenoceptors at nanomolar to submicromolar range. Some compounds were moderately selective ligands of alpha(1)-adrenoceptors. Selected compounds (3a-5a, 7a, 13a, 14a) were also evaluated for their alpha(1)-adrenoceptor antagonistic properties in functional bioassays. A SAR study indicated that the most active compounds contain 2-alkoxyphenylpiperazine moieties and methyl or 2-methylpropionate substituent at 3-N position in hydantoin. The exchange of 2-alkoxyphenyl moiety into 2-furoyl or 2-pyridyl group significantly decreased affinities for alpha(1)-adrenoceptors. Molecular modelling results obtained using conformational analysis CONFLEX and PM5 method for geometry optimization, allowed for comparison of the spatial properties of tested compounds with pharmacophore model created by Barbaro et al. for the ideal alpha(1)-adrenoceptor antagonist.

Synthesis and pharmacological evaluation of new 1-[3-(4-arylpiperazin-1-yl)-2-hydroxypropyl]-pyrrolidin-2-one derivatives with anti-arrhythmic, hypotensive, and alpha-adrenolytic activity.

A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment was synthesized and evaluated for the binding affinity of the alpha(1)- and alpha(2)-adrenoceptors (AR) and for the antiarrhythmic and hypotensive activities of the compounds. The most potent and selective compound 1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one 8 binds with pK(i) = 6.71 for alpha(1)-AR. Derivative 8 was also the most active in the prophylactic antiarrhythmic test in adrenaline-induced arrhythmia in anaesthetized rats. Its ED(50 )value equals 1.9 mg/kg (i.v.). Compounds with substituents such as a fluorine atom 4, a methyl 5, or a hydroxyl 8 group, or two substituents such as fluorine/chlorine atoms and methoxy groups in the phenyl ring, significantly decreased the systolic and diastolic pressure in normotensive anesthetized rats at a dosages of 5-10 mg/kg (i.v.). It was found that the presence of the piperazine ring and a hydroxy group in the second position of the propyl chain are critical structural features in determining the affinity of the compounds tested.

Design, synthesis and pharmacological evaluation of alpha-substituted N-benzylamides of gamma-hydroxybutyric acid with potential GABA-ergic activity. Part 6. Search for new anticonvulsant compounds.

In the recent study we have extended our investigations to the new anticonvulsant derivatives of alpha-substituted N-benzylamides of gamma-hydroxybutyric acid (GHB). Among the obtained compounds N-benzylamide of alpha-(1,2,3,4-tetrahydroisoquinoline)-GHB (9) has demonstrated activity against maximal electroshock (MES) induced seizures in mice (at 100 mg/kg ip) and in rats (at 30 mg/kg, po dose). Lactone 8 and amide 9 have possessed a weak effect on [3H]-muscimol binding. Molecular modeling studies have revealed that anticonvulsant activity of the alpha-substituted amides of GHB might partially be explained by the orientation of the terminal benzylamide fragment.

Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development.

Neonatal (postnatal days 8-21) exposure of rats to the selective serotonin reuptake inhibitor (SSRI), citalopram, results in persistent changes in behavior including decreased sexual activity in adult animals. We hypothesized that this effect was a consequence of abnormal stimulation of 5-HT(1A) and/or 5-HT(1B) receptors as a result of increased synaptic availability of serotonin during a critical period of development. We examined whether neonatal exposure to a 5-HT(1A) (8OH-DPAT) or a 5-HT(1B) (CGS 12066B) receptor agonist can mimic the effect of neonatal exposure to citalopram on adult sexual behavior. Results showed that neonatal treatment with 5-HT(1B) receptor agonist robustly impaired sexual behavior similar to the effect of citalopram, whereas exposure to 5-HT(1A) receptor agonist only moderately influenced male sexual activity in adult animals. These data support the hypothesis that stimulation of serotonin autoreceptors during development contributes to the adult sexual deficit in rats neonatally exposed to citalopram.

Medium supplementation with zinc enables detection of imipramine-induced adaptation in glycine/NMDA receptors labeled with [3H]L-689,560.

Antidepressant drugs after chronic administration induce adaptive changes in the NMDA receptor complex. Radioligand-receptorbinding studies using [3H]5,7-dichlorokynurenic acid demonstrated a "down-regulation" of the glycine site/NMDA receptor following chronic treatment with antidepressants and electroconvulsive shock. However, binding procedure using this radioligand is time consuming because it requires the use of centrifugation method in the separation process. The introduction of a new radioligand of glycine/NMDA receptor, [3H]L-689,560 enables the application of a rapid filtration method. In the present study we demonstrate that 2-week treatment with imipramine (15 mg/kg ip) did not evoke alterations in specific [3H]L-689,560 binding and in IC50 value of glycine in displacing [3H]L-689,560 binding in the mouse or rat cortex. However, longer, a 4-week treatment with imipramine induced a significant 71% increase in IC50 value in displacing [3H]L-689.560 binding in the mouse cortex. Moreover, the presence of zinc in the incubation media, dose-dependently enhances detection of imipramine-induced increase in IC50 value of glycine in displacing [3H]L-689,560 binding in the rat cortex. The present data indicate that: (1) [3H]L-689,560 may be a suitable ligand for assessing adaptation of the glycine/NMDA sites and (2) the presence of zinc enhances detection of imipramine-induced reduction of glycine affinity for glycine/NMDA receptors labeled with [3H]L-689,560 which further indicates a significance of zinc in the mechanism of antidepressant treatment.

Synthesis, physicochemical and anticonvulsant properties of new N-(pyridine-2-yl) derivatives of 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione. Part II.

A series of N-(pyridine-2-yl) derivatives of 2-azaspiro[4.4]nonane- (1a-e), 2-azaspiro[4.5]decane- (2a-e) and 6-methyl-2-azaspiro[4.5]decane-1,3-dione (3a-e) were synthesized and tested for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. To explain the possible mechanism of action, the most active compounds N-(3-methylpyridine-2-yl)-2-azaspiro[4.4]nonane-1,3-dione (1b), N-(3-methylpyridine-2-yl)-2-azaspiro[4.5]decane-1,3-dione (2b), N-(4-methylpyridine-2-yl)-2-azaspiro[4.5]decane-1,3-dione (2c), and N-(3-methylpyridine-2-yl)-6-methyl-2-azaspiro[4.5]decane-1,3-dione (3b) were tested in vitro for their influence on voltage-sensitive calcium channel receptors, however, they revealed low affinities. For all synthesized compounds the lipophilicity was determined by use of RP-TLC method. The correlation between the lipophilicity and anticonvulsant activity was obtained--the higher the lipophilicity the stronger the anticonvulsant efficacy.

Neonatal citalopram exposure produces lasting changes in behavior which are reversed by adult imipramine treatment.

Neonatal exposure to antidepressants, including selective serotonin reuptake inhibitors such as citalopram, induces behavioral disturbances which persist in mature rats. These disturbances have been proposed to model the symptoms of endogenous depression. However, to date there is scant evidence for the predictive validity of any of these behaviors in response to adult antidepressant treatments. In order to directly assess the predictive validity of the early antidepressant exposure paradigm, the present study examined whether the behavioral abnormalities observed in adult animals exposed as neonates to citalopram can be reversed by adult antidepressant treatment with the prototypic antidepressant, imipramine. As noted earlier, neonatal citalopram exposure robustly increased locomotor activity and impaired male sexual behavior in adult rats. These behavioral changes were reversed following chronic adult imipramine treatment. No such reversal was observed in handled, saline treated rats. The present data support the hypothesis that some of the lasting behavioral abnormalities induced by early antidepressant exposure are sensitive to clinically relevant antidepressant treatments thus adding a measure of predictive validity to this paradigm as a model of these depressive symptoms.

Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry.

A significant fraction of infants born to mothers taking selective serotonin reuptake inhibitors (SSRIs) during late pregnancy display clear signs of antidepressant withdrawal indicating that these drugs can penetrate fetal brain in utero at biologically significant levels. Previous studies in rodents have demonstrated that early exposure to some antidepressants can result in persistent abnormalities in adult behavior and indices of monoaminergic activity. Here, we show that chronic neonatal (postnatal days 8-21) exposure to citalopram (5 mg/kg, twice daily, s.c.), a potent and highly selective SSRI, results in profound reductions in both the rate-limiting serotonin synthetic enzyme (tryptophan hydroxylase) in dorsal raphe and in serotonin transporter expression in cortex that persist into adulthood. Furthermore, neonatal exposure to citalopram produces selective changes in behavior in adult rats including increased locomotor activity and decreased sexual behavior similar to that previously reported for antidepressants that are nonselective monoamine transport inhibitors. These data indicate that the previously reported neurobehavioral effects of antidepressants are a consequence of their effects on the serotonin transporter. Moreover, these data argue that exposure to SSRIs at an early age can disrupt the normal maturation of the serotonin system and alter serotonin-dependent neuronal processes. It is not known whether this effect of SSRIs is paralleled in humans; however, these data suggest that in utero, exposure to SSRIs may have unforeseen long-term neurobehavioral consequences.

Synthesis and development of new 2-substituted 1-[3-(4-arylpiperazin-1-yl)propyl]-pyrrolidin-2-one derivatives with antiarrhythmic, hypotensive, and alpha-adrenolytic activity.

A series of new 1-[3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a-12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the alpha1- and alpha2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2.7 mg kg(-1), and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected alpha1-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands.

Synthesis and evaluation of in vivo activity of diphenylhydantoin basic derivatives.

During the search for antiarrhythmic agents among amide derivatives of phenytoin, compound 7 {3-ethyl-1-[2-hydroxy-3-(4-phenyl-piperazin-1-yl)-propyl]-2,4-dioxo-5,5-diphenyl-imidazolidine} was selected as it showed antiarrhythmic as well as antihypertensive activity. Treating this compound as a lead, new derivatives 8-19 were synthesised, differing in piperazine phenyl ring substitution (2-, 3-, 4-Cl, 2-CH3O) as well as in hydantoin N3 alkyl chain (ethyl, ethyl acetate or ethyl 2-propionate). The obtained compounds in form of hydrochlorides 7a-19a were examined for prophylactic antiarrhythmic and antihypertensive properties. Compounds containing ethyl 2-propionate moiety (17a, 18a) exhibited the highest antihypertensive properties. Water-soluble compounds, containing 2-methoxyphenylpiperazine group (11a, 19a), showed strong antiarrhythmic properties in adrenaline-induced arrhythmia; compound 9a {1-[3-(4-(3-chloro-phenyl)-piperazin-1-yl)- 2-hydroxy-propyl]- 3-ethyl-2,4-dioxo-5,5-diphenyl-imidazolidine hydrochloride} exhibited the highest antiarrhythmic activity in barium chloride arrhythmia model.

New arylpiperazine 5-HT(1A) receptor ligands containing the pyrimido[2,1-f]purine fragment: synthesis, in vitro, and in vivo pharmacological evaluation.

New 1H,3H-pyrimido[2,1-f]purine-2,4-dione derivatives of arylpiperazine (11-22) were prepared and evaluated in vitro for their affinity for 5-HT(1A), 5-HT(2A), alpha(1), and D(2) receptors. The tested compounds showed high affinity for 5-HT(1A) and alpha(1) receptors (K(i) = 1.1-87 and 10-62 nM, respectively) and moderate to low affinity for 5-HT(2A) (K(i) = 56-881 nM) and D(2) receptors (K(i) = 94-1245 nM). Compounds 14, 15, 18, 19, and 21, mostly 3'-chlorophenylpiperazine derivatives, can be classified as mixed 5-HT(1A)/5-HT(2A)/alpha(1) ligands. Compound 13, which showed the highest 5-HT(1A) receptor affinity (K(i) = 1.1 nM), was 50-fold selective in relation to alpha(1) adrenoceptors and at least 250-fold over 5-HT(2A) and D(2) sites. On the basis of in vivo functional tests, 8-phenylpiperazinoethylamino (11), 8-(2'-methoxyphenylpiperazino)ethylamino (13), and 8-phenylpiperazinopropylamino (14) derivatives of 1,3-dimethyl-1H,3H-pyrimido[2,1-f]purine-2,4-dione were identified as potent pre- and postsynaptic 5-HT(1A) receptor antagonists. 1,3-Dimethyl-7-bromo-8-(phenylpiperazinopropylamino)-1H,3H-pyrimido[2,1-f]purine-2,4-dione (20) behaved like an agonist of presynaptic and as a partial agonist of postsynaptic 5-HT(1A) receptors and resembled ipsapirone in terms of functional intrinsic activity. It revealed marked anxiolytic-like activity in the Vogel test in rats, comparable to that of the reference drug diazepam, and exhibited antidepressant-like activity in the Porsolt test in rats. The sedative effect of 20, evaluated in the open field test in rats, appeared at doses twice as high as those inducing a minimal anxiolytic-like effect and was similar to the effects of diazepam.

Synthesis and pharmacological properties of N,N-dialkyl(dialkenyl)amides of 7-methyl-3-phenyl-1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid.

Synthesis of N,N-dialkyl(dialkenyl)amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (5-9) and their 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl] derivatives (10-14) is described. Compounds 10-14 were tested for analgesic and sedative activities as well as for mu-opioid receptors binding affinities. All the amides, being the object of investigation, displayed an interesting analgesic action, which in case of the compounds 10-12 and 14 was superior to that of acetylsalicylic acid in two different tests. Furthermore all the amides (10-14) significantly suppressed the spontaneous locomotor activity, prolonged barbiturate sleep in mice and showed a weak affinity to mu-opioid receptors.