Biomedical subjects

Michael Schwarz

Publications and source records attributed to Michael Schwarz.

At least 37 records · Page 2Linked to original sources

PubMed2005

Model based prognosis of postoperative object naming in left temporal lobe epilepsy.

Epilepsy surgery in the left temporal lobe is associated with a high risk of naming decline. In the present study, in 45 patients with left temporal lobe epilepsy (TLE) and confirmed left hemisphere language dominance, 13 (29%) patients demonstrated postoperative decrement >or=5 naming failures in the Boston Naming Test (BNT). Multivariate discriminant analysis with age at onset of epilepsy, age at first risk, age at operation and preoperative naming performance as predictors indicated that 12 (92%) patients with later naming decline could be identified preoperatively. Univariate group comparisons revealed that specifically patients with seizure onset later than 14 years without preceding risk factors (e.g., febrile seizures) are in danger of postoperative dysnomia. It is hypothesized, that there is a strong connection between stable naming performance and deviant intrahemispheric speech representation as a result of early brain damage and/or chronic seizures.

Adult↗

PubMed2005

Effect of copigments and grape cultivar on the color of red wines fermented after the addition of copigments.

The prefermentation addition of copigments led to significantly different red wines according to the copigment structure (flavonol or hydroxycinnamic acid) and the grape cultivar [Tempranillo (= Cencibel) or Cabernet Sauvignon]. The flavonol rutin enhanced copigmentation and anthocyanin extraction, improving the red color, but the hydroxycinnamic acids (especially caffeic acid) had converse results. The above effects were higher in Cabernet Sauvignon wines, particularly if rutin or p-coumaric acid was used. These wines showed the highest copigmentation as they contained more anthocyanins and flavonols, whereas the coumaroylated anthocyanins of Tempranillo wines could have prevented the action of the added copigments. After 21 months, the main pyranoanthocyanins found were the malvidin-3-glucoside 4-vinylphenol and the malvidin-3-glucoside 4-vinylcatechol (pinotin A) adducts. The results suggested that the former adduct was primarily generated following enzymatic decarboxylation of p-coumaric acid during fermentation, whereas pinotin A was formed through a pure chemical reaction, which depended on the concentration of free caffeic acid during aging.

Anthocyanins↗

PubMed2005

Effect of the tumor promoter phenobarbital on the pattern of global gene expression in liver of connexin32-wild-type and connexin32-deficient mice.

The antiepileptic drug phenobarbital (PB) is used frequently as a model tumor promoter in rodent liver. It is believed to increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. The molecular mechanism underlying this process is only partly understood but seems to require the function of connexin32 (Cx32), one of the 2 gap junction proteins expressed in hepatocytes. PB mediates transcriptional activation of various genes in liver but which of these are relevant for tumor promotion is unknown. We have used oligonucleotide microarrays to identify genes differentially modulated in expression by PB in liver of Cx32-wild-type and Cx32-null mice. Mice of both strains were kept on PB containing (0.05%) or control diet for 2 weeks. Total liver RNA was isolated from 3 mice per experimental group and reverse transcribed; cDNAs were hybridized to oligonucleotide microarrays and a gene-by-gene linear model was used for statistical analysis of data. Five genes were identified as induced or repressed in untreated Cx32-null as compared to untreated Cx32-wild-type mice. PB affected the expression of 53 genes, of which 13 code for members of Phase-I/II of drug metabolism, and 12 genes were differentially affected in expression by PB in Cx32-null as compared to Cx32-wild-type mice. Among the differentially affected genes that could be verified by quantitative RT-PCR or Western analysis were the insulin like growth factor binding protein-1, retinol dehydrogenase-6 and the Y-chromosomally located gene Dby, among which may be a candidate of relevance for PB-mediated tumor promotion.

Animals↗

PubMed2005

Characterization of pigments from different high speed countercurrent chromatography wine fractions.

A red wine, made from Cabernet Sauvignon (60%) and Tannat (40%) cultivars, was fractionated by high speed countercurrent chromatography (HSCCC). The biphasic solvent system consisting of tert-butyl methyl ether/n-butanol/acetonitrile/water (2/2/1/5, acidified with 0.1% trifluoroacetic acid) was chosen for its demonstrated efficiency in separating anthocyanins. The different native and derived anthocyanins were identified on the basis of their UV-visible spectra, their elution time on reversed-phase high-performance liquid chromatography (HPLC), and their mass spectra, before and after thiolysis. The HSCCC method allowed the separation of different families of anthocyanin-derived pigments that were eluted in different fractions according to their structures. The hydrosoluble fraction was almost devoid of native anthocyanins. Further characterization (glucose quantification, UV-visible absorbance measurements) indicated that it contained flavanol and anthocyanin copolymers in which parts of the anthocyanin units were in colorless forms. Pigments in the hydrosoluble fraction showed increased resistance to sulfite bleaching and to the nucleophilic attack of water.

Anthocyanins↗

PubMed2005

Role of MRI in the management of children with diffuse pontine tumors: a study of 15 patients and review of the literature.

BACKGROUND: Pontine tumors carry the worst prognosis of all brain tumors. In most cases, the diagnosis is based solely on MR imaging, without biopsy. OBJECTIVE: To describe the MR findings of pontine tumors at diagnosis and during follow-up and correlate those with prognosis and to assess the value of MR imaging in patient management compared to clinical evaluation. MATERIALS AND METHODS: Ninety-one MR scans of 15 children with diffuse pontine tumors were reviewed at diagnosis and during follow-up. The parameters analyzed were as follows: tumor extent, area, and volume; encasement of the basilar artery; presence of exophytic component; necrosis; cysts; hydrocephalus; and intensity and enhancement. Findings were correlated to length of progression-free and overall survival. Trends of amelioration or worsening on imaging were compared with the clinical findings. RESULTS: Median length of progression-free survival was 10 months, and median survival was 20 months. Only hydrocephalus at presentation was associated with shorter progression-free survival (P=0.02). On the last examination of each patient, the craniocaudal diameter was significantly greater than at diagnosis (P=0.03). The concordance between the imaging and the clinical findings was good. CONCLUSION: MR is the mainstay for the diagnosis and management of pontine tumors. Cranial growth seems to be an ominous sign. However, the prognostic value of MR is limited. MR findings correlate well with the clinical examination.

Adolescent↗

PubMed2005

Human p53 knock-in (hupki) mice do not differ in liver tumor response from their counterparts with murine p53.

Mouse models are important tools in toxicologic research. Differences between species in pathways contributing to tumor development, however, raise the question in how far mouse models are valid for human risk assessment. One striking difference relates to the frequency of spontaneous liver cancer which is high in certain mouse strains but rather low in humans. Similarly, mutation frequencies in cancer genes are characteristically different, i.e. P53 mutations are frequent in human but very rare in murine liver tumors, whereas Ras genes are often mutated in mouse liver tumors but hardly ever in human liver cancers. Since P53 has been shown to control oncogenic RAS in human cells, we hypothesized that this function of the tumor suppressor could differ in mouse hepatocytes. To test this hypothesis, we used hupki (human p53 knock-in) mice which carry a partly humanized P53 sequence (P53KI). In this study, we report the results of the first hepatocarcinogenesis experiment with this strain of mice. Mice of the genotypes P53KI/KI, P53WT/KI and P53WT/WT were treated with N-nitrosodiethylamine at 2 weeks of age and killed 35 weeks later. The frequency of liver tumors and glucose-6-phosphatase-altered liver lesions was almost identical in all three P53 genotypes and approximately 40-50% of liver tumors showed activating mutations in codon 61 of the Ha-Ras gene independent of genotype. Moreover, only very few P53-positive lesions were observed but without nuclear localization of the protein, suggesting the absence of P53 mutations. These data suggest that the hupki allele behaves like its murine ortholog in mouse hepatocarcinogenesis.

Animals↗

PubMed2005

Modulation of liver tumorigenesis in Connexin32-deficient mouse.

Connexin32 (Cx32) is the major gap junction forming protein in liver. Mice deficient in Cx32 demonstrate enhanced liver tumor formation, but are resistant to promotion of hepatocarcinogenesis by the model tumor promoter phenobarbital (PB). Here, we re-evaluate data on the number and sizes of glucose-6-phosphatase (G6Pase)-deficient liver lesions, both in Cx32-wildtype (WT) and Cx32-null male mice, obtained from two earlier experiments with similar protocols but paradoxical outcomes. In these experiments, enzyme-altered lesions were induced in mice of both strains by a single injection of N-nitrosodiethylamine (DEN) at age 6 weeks with a dose of 90 microg/g body weight (experiment 1) or at age 2 weeks with 10 microg/g body weight (experiment 2). Three weeks after DEN treatment groups of mice (sub-divided by Cx32 status) were also started on a PB-containing (0.05%) diet to test the responsiveness of the lesions to the tumor promoter. Additionally, for experiment 1, tumors were analyzed for the presence of Ha-ras and beta-catenin mutations. Based on the mutational analysis and the mathematical analysis of the G6Pase-deficient lesions, the two studies are consistent with the hypothesis of two types of lesions, 'late-type' lesions which are mainly characterized by beta-catenin mutations, and 'early-type' lesions that are frequently (but not exclusively) Ha-ras mutated. This concept affords an explanation as to the differential response seen in the two experiments with regard to Cx32 status and the role of PB as a tumor promoter (experiment 1) or inhibitor (as in experiment 2). Our findings also underscore the importance of the timing (6 weeks versus 2 weeks) of the genotoxic insult in relation to the developmental stage of the liver and the importance of clonal selection during tumor promotion.

Age Factors↗

PubMed2005

B-raf and Ha-ras mutations in chemically induced mouse liver tumors.

The mitogen-activated protein kinase signalling pathway is a central regulator of tumor growth, which is constitutively activated in chemically induced mouse liver tumors. In about 30-50% of cases this effect can be related to activation of the Ha-ras gene by point mutations, whereas in the remaining cases mutations may occur in other members within this pathway, such as Raf kinases. Recently, B-raf has been shown to be frequently mutated in human melanomas and certain other cancers, with a V599E amino-acid change representing the most predominant mutation type. We now screened 82 N-nitrosodiethylamine-induced liver tumors from C3H/He mice for mutations within the hotspot positions in the Ha-ras and B-raf genes. About 50% (39/82) of tumors showed Ha-ras codon 61 mutations and 16 tumors ( approximately 20%) harbored mutations at codon 624 of the B-raf gene, which corresponds to codon 599 in human B-raf. None of the tumors was mutated in both Ha-ras and B-raf. The high prevalence of Ha-ras and B-raf mutations in mouse liver tumors is in striking contrast to human hepatocellular cancers which very infrequently harbor mutations in the two genes. These fundamental differences between the biology of liver tumors in mice and man may be of toxicological relevance.

Animals↗

PubMed2005

Genotype-phenotype relationships in hepatocellular tumors from mice and man.

Experimentally induced liver tumors in mice harbor activating mutations in either Catnb (beta-catenin) or Ha-ras, according to the carcinogenic treatment. We have now investigated by microarray analysis the gene expression profiles in tumors of the two genotypes. In total, 364 genes or expressed sequences with aberrant expression relative to normal liver were identified, but only 30 of these demonstrated unidirectional changes in both tumor types. Several functional clusters were identified that involve changes in amino acid utilization and ammonia disposition in Catnb-mutated tumors as opposed to alterations in lipid and cholesterol metabolism in Ha-ras-mutated tumors. Moreover, several genes coding for inhibitory molecules within the Wnt-signaling pathway were upregulated in Catnb-mutated tumors, suggesting induction of a negative feedback loop, whereas Ha-ras-mutated tumors showed alterations in the expression of several genes functional in monomeric G-protein signaling. We conclude that mouse hepatoma cells adopt different evolutionary strategies that allow for their selective outgrowth under variable environmental conditions. Human hepatocellular cancers (HCC) lack RAS mutations but are frequently mutated in CTNNB1, the human Catnb ortholog. The set of genes aberrantly expressed in Catnb-mutated mouse tumors was used to screen, by expression profiling, for dysregulation of orthologous genes within a panel of 25 HCCs, of which 10 were CTNNB1-mutated. HCCs with activated beta-catenin displayed a gene expression profile that was similar to Catnb-mutated mouse tumors but distinct from the other human HCCs. In conclusion, expression fingerprints may be used for diagnostic purposes and potential new therapeutic intervention strategies. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index/html).

Animals↗

PubMed2005

Carcinogenic risks of dioxin: mechanistic considerations.

Dioxins and dioxin-like chemicals demonstrate high affinity binding to the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, which mediates most, if not all, of the toxic responses of these agents. Since dioxins are not directly genotoxic their carcinogenic effect is likely the result of their tumor promoting activity produced by activation of the AhR. For the purpose of risk assessment extrapolation from effects in the observable high dose range to background dietary exposure is necessary. In the present review, we discuss various aspects of low-dose-response of receptor-mediated processes in general, including threshold phenomena with regard to tumor promotion during multi-stage carcinogenesis. In this connection the reversibility of tumor promotion plays an important role but this may not be valid for dioxins due to their long half life. The relevance of cytochrome P 4501 A-induction as biomarker for prediction of carcinogenic effects of dioxins at low doses is considered. Dioxins may act in concert with endogenous ligands of the AhR, an effect which becomes particularly relevant at low toxicant concentrations. At present, however, the nature and role of these postulated ligands are unknown. Furthermore, it is unclear whether dioxins produce synergistic tumor promotional effects with non-dioxin-like chemicals to which humans are also exposed. Dioxins and, e.g., non-dioxin-like PCBs act through different receptors and there is, albeit yet limited, experimental evidence from experimental studies to suggest that they may act on different target cell populations within the same target organ. From the available data the existence of a (physiological) threshold of effects cannot be proven and may not even exist. For regulatory purposes the application of a so called "practical threshold" for the carcinogenic effect of dioxins is proposed. Further mechanistic studies should be conducted to get insight into the dose-response characteristics of relevant events of dioxin-like and non-dioxin-like agents and into the consequences of potential interactions between both group of compounds during carcinogenesis.

Animals↗

PubMed2005

Differential involvement of the cerebellum in biological and coherent motion perception.

Perception of biological motion (BM) is a fundamental property of the human visual system. It is as yet unclear which role the cerebellum plays with respect to the perceptual analysis of BM represented as point-light displays. Imaging studies investigating BM perception revealed inconsistent results concerning cerebellar contribution. The present study aimed to explore the role of the cerebellum in the perception of BM by testing the performance of BM perception in patients suffering from circumscribed cerebellar lesions and comparing their performance with an age-matched control group. Perceptual performance was investigated in an experimental task testing the threshold to detect BM masked by scrambled motion and a control task testing the detection of motion direction of coherent motion masked by random noise. Results show clear evidence for a differential contribution of the cerebellum to the perceptual analysis of coherent motion compared with BM. Whereas the ability to detect BM masked by scrambled motion was unaffected in the patient group, their ability to discriminate the direction of coherent motion in random noise was substantially affected. We conclude that intact cerebellar function is not a prerequisite for a preserved ability to detect BM. Because the dorsal motion pathway as well as the ventral form pathway contribute to the visual perception of BM, the question of whether cerebellar dysfunction affecting the dorsal pathway is compensated for by the unaffected ventral pathway or whether perceptual analysis of BM is performed completely without cerebellar contribution remains to be determined.

Adult↗

PubMed2005

Thiamine deficiency in infants: MR findings in the brain.

BACKGROUND AND PURPOSE: Thiamine deficiency is extremely rare in infants in developed countries. To our knowledge, its MR findings in the brain have not been reported. The purpose of this study was to investigate the brain MR findings in infants with encephalopathy due to thiamine deficiency. METHODS: The study group included six infants aged 2-10 months with encephalopathy who had been fed with solely soy-based formula devoid of thiamine from birth. All underwent MR evaluation at admission and follow-up (total of 14 examinations). In one patient, MR spectroscopy (MRS) was performed. RESULTS: In five patients T2-weighted, fluid-attenuated inversion recovery, or proton-attenuated sequences showed bilateral and symmetric hyperintensity in the periaqueductal area, basal ganglia and thalami. Five had lesions in the mammillary bodies, and three, in the brain stem. In all six patients, the frontal region (cortex and white matter) was clearly involved. At presentation, MRS of the periaqueductal area showed a lactate doublet. On long-term follow-up, three of four patients had severe frontal damage; in two, this occurred as part of diffuse parenchymal loss, and in one, it was accompanied by atrophy of the basal ganglia and thalami. CONCLUSION: Thiamine deficiency in infants is characterized by involvement of the frontal lobes and basal ganglia, in addition to the lesions in the periaqueductal region, thalami, and the mammillary bodies described in adults. MRS demonstrates a characteristic lactate peak.

Brain↗

PubMed2004

Characterization of anthocyanins and pyranoanthocyanins from blood orange [Citrus sinensis (L.) Osbeck] juice.

Anthocyanins from blood orange [Citrus sinensis (L.) Osbeck] juices were isolated and purified by means of high-speed countercurrent chromatography and preparative high-performance liquid chromatography. Structures of the pigments were then elucidated by electrospray ionization multiple mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. The major anthocyanins of the juice were characterized as cyanidin 3-glucoside and cyanidin 3-(6"-malonylglucoside). Furthermore, six minor anthocyanins were detected and identified as cyanidin 3,5-diglucoside, delphinidin 3-glucoside, cyanidin 3-sophoroside, delphinidin 3-(6"-malonylglucoside), peonidin 3-(6"-malonylglucoside), and cyanidin 3-(6"-dioxalylglucoside). The occurrence of the latter compound in blood oranges is reported here for the first time, together with full NMR spectroscopic data. Further investigations revealed the presence of four anthocyanin-derived pigments, which are formed through a direct reaction between anthocyanins and hydroxycinnamic acids during prolonged storage of the juice. These novel pyranoanthocyanins were identified as the 4-vinylphenol, 4-vinylcatechol, 4-vinylguaiacol, and 4-vinylsyringol adducts of cyanidin 3-glucoside through comparison of their mass spectrometric and chromatographic properties with those of synthesized reference compounds.

Anthocyanins↗

PubMed2004

Insulin and dexamethasone inhibit TGF-beta-induced apoptosis of hepatoma cells upstream of the caspase activation cascade.

Insulin and dexamethasone are potent inhibitors of apoptosis induced by transforming growth factor-beta1 (TGF-beta) in hepatoma cells. Using FTO-2B rat hepatoma cells, we determined whether the anti-apoptotic effects of these agents result from interference within or upstream of the TGF-beta-induced caspase cascade. Activation of different initiator and effector caspases, Bax and Bcl-xL expression, mitochondrial cytochrome c release and activation of PKB/Akt were analyzed by use of synthetic caspase substrates and Western blotting, respectively. TGF-beta-induced apoptosis was characterized by release of cytochrome c from mitochondria and activation of caspases-3, -7, -8 and -9. These effects were observable as early as 8-12 h after start of treatment and increased with time of observation. Inhibition of TGF-beta-induced apoptosis by insulin and dexamethasone was paralleled by a strong reduction of caspase-3-like activity. Caspase-8 activation was almost completely suppressed by these agents, and caspase-9 activity was decreased to levels within or slightly above unstimulated control cells. In addition, cytochrome c release from mitochondria was efficiently repressed, which was associated with upregulation of Bcl-xL by dexamethasone and activation of PKB/Akt by insulin. Thus, both anti-apoptotic compounds exert their inhibitory effects through modulation of anti-apoptotic signalling pathways involved in regulation of cytochrome c release and activation of the caspase machinery.

Animals↗

PubMed2004

Do normal D-dimer levels reliably exclude cerebral sinus thrombosis?

BACKGROUND AND PURPOSE: Cerebral sinus thrombosis (CST) needs to be considered in the differential diagnosis of all patients with acute headache. Early diagnosis is essential because early treatment may prevent morbidity and may even be life-saving. Definite exclusion, however, needs advanced neuroradiologic diagnostics, which are not readily available in many hospitals. Because measurement of D-dimers has been demonstrated to be helpful in excluding thromboembolic disease, our aim was to investigate whether D-dimers would be also sensitive enough to exclude CST. METHODS: We undertook a prospective multicenter study over a 2.5-year period including all patients who came to the emergency departments with symptoms suggestive of CST. All patients were diagnosed either by magnetic resonance venography, spiral computed tomography scan venography, or intra-arterial digital subtraction angiography. D-dimer levels were measured at admission and analyzed by the same method in all patients. RESULTS: A total of 343 patients were included. CST was diagnosed in 35 patients, of whom 34 had D-dimers above the cutoff value (>500 microg/L). From the 308 patients not having CST, D-dimers were elevated in 27. Sensitivity of D-dimers was 97.1%, with a negative predictive value of 99.6%. Specificity was 91.2%, with a positive predictive value of 55.7%. D-dimers were positively correlated with the extent of the thrombosis and negatively correlated with the duration of symptoms (Spearman rank correlation coefficients 0.76, -0.58, respectively). CONCLUSIONS: D-dimer measurement is useful in patients with suspected CST. Normal D-dimers make the presence of CST very unlikely.

Adult↗

PubMed2004

Clinical and sonographic criteria of acute scrotum in children: a retrospective study of 172 boys.

BACKGROUND: Diagnosis of testicular torsion in children is challenging, as clinical presentation and findings may overlap with other diagnoses. OBJECTIVE: To define the clinical and ultrasound criteria that best predict testicular torsion. MATERIALS AND METHODS: The records of children hospitalized for acute scrotum from 1997 to 2002 were reviewed. The clinical and ultrasound findings of children who had a final diagnosis of testicular torsion were compared with those of children who had other diagnoses (torsion of the testicular appendix, epididymitis, and epididymo-orchitis). RESULTS: Forty-one children had testicular torsion; 131 had other diagnoses. Stepwise regression analysis yielded three factors that were significantly associated with testicular torsion: duration of pain < or =6 h; absent or decreased cremasteric reflex; and diffuse testicular tenderness. When the children were scored by final diagnosis for the presence of these factors (0-3), none of the children with a score of 0 had testicular torsion, whereas 87% with a score of 3 did. The ultrasound finding of decreased or absent testicular flow had a sensitivity of 63% and a specificity of 99%. Eight of ten children with testicular torsion and normal or increased testicular flow had a coiled spermatic cord on ultrasound. CONCLUSION: We suggest that all children with acute scrotal pain and a clinical score of 3 should undergo testicular exploration, and children with a lower probability of testicular torsion (score 1 or 2) should first undergo diagnostic ultrasound. Because the presence of testicular flow does not exclude torsion, the spermatic cord should be meticulously evaluated in all children with acute scrotum and normal or increased testicular blood flow.

Acute Disease↗

PubMed2004

A beta-catenin-dependent pathway regulates expression of cytochrome P450 isoforms in mouse liver tumors.

Phenobarbital (PB) is a model tumor promoter in the rodent liver. In the mouse, the promotional effect of PB results from a selective stimulation of clonal outgrowth of hepatocytes harboring activating mutations in the beta-catenin (catnb) gene. Glutamine synthetase (GS), a downstream target in the Wnt/beta-catenin/T-cell factor (TCF) signaling pathway, is strongly up-regulated in catnb-mutated mouse liver tumors and may serve as a marker for their identification. Here we show that the levels of several cytochrome P450 (CYP) isoenzymes are also altered in GS-positive liver tumors. Immunohistochemical and western blotting analyses demonstrated that GS-positive, catnb-mutated tumors showed levels of CYP1A, CYP2B, CYP2C and CYP2E1, which were similar or slightly enhanced in comparison with non-tumoral liver tissue. This contrasts with tumors without catnb mutations, which exhibited decreased levels of these CYP isoforms. Real-time RT-PCR revealed that the differences in CYP levels in the tumors corresponded to changes in the respective mRNAs. Mouse hepatoma cells were transiently transfected with an expression vector encoding an S33Y-mutated beta-catenin protein, which was functional with regard to transactivation of a beta-catenin/TCF-responsive (topflash) reporter construct. Co-transfected with luciferase reporter vectors containing either the regulatory upstream sequence of the CYP2B1 gene or three dioxin-responsive core elements were activated by S33Y-beta-catenin. These results indicate that mutation of catnb leads to transcriptional activation of CYP isoenzymes in mouse liver tumors. As CYPs are involved in both the activation and the inactivation of several clinically important anticancer drugs, our findings may be relevant for chemotherapy of human cancers, where activation of beta-catenin-dependent signaling by mutation of the gene or alternative mechanisms is frequently observed.

Animals↗

PubMed2004

Dual 5-HT1A agonists and 5-HT re-uptake inhibitors by combination of indole-butyl-amine and chromenonyl-piperazine structural elements in a single molecular entity.

The dual serotonin (5-HT) re-uptake inhibitor and 5-HT(1A) receptor agonist vilazodone was found to increase central serotonin levels in rat brain. In the course of structural modifications of vilazodone 3-[4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinyl]-butyl]-1H-indole-5-carbonitrile 8i and its fluorine analogue 6-[4-[4-(5-fluor-3-indolyl)-butyl]-1-piperazinyl]-2H-1-benzopyran-2-one have been identified. These unsubstituted chromenones are equally potent at the 5-HT(1A) receptor and 5-HT transporter. The implementation of nitrogen functionalities in position 3 of the chromenones resulted in compounds acting as agonists at the 5-HT(1A) receptor and as 5-HT re-uptake inhibitors like vilazodone. Ex vivo 5-HT re-uptake inhibition and in vitro 5-HT agonism were determined in the PCA- and GTPgammaS-assay, respectively. The potential of these chromenones to increase central 5-HT levels was measured in microdialysis studies and especially the derivatives 3-[4-[4-(3-amino-2-oxo-2H-chromen-6-yl)-piperazin-1-yl]-butyl]-1H-indole-5-carbonitrile 8f, ethyl (6-[4-[4-(5-cyano-1H-indol-3-yl)-butyl]-piperazin-1-yl]-2-oxo-2H-chromen-3-yl)-carbamate 8h and N-(6-[4-[4-(5-cyano-1H-indol-3-yl)-butyl]-piperazin-1-yl]-2-oxo-2H-chromen-3-yl)-acetamide 8k give rise to rapid development of increased serotonin levels in rat brain cortex, lasting longer than 3h.

Animals↗