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Increasing evidence accumulates that metabolites of the dissociative anesthetic ketamine contribute considerably to the biological effects of this drug and could be developed as next generation antidepressants, especially for acute treatment of patients with therapy-refractory major depression. Analytical methods for the simultaneous determination of the plethora of hydroxylated, dehydrogenated and/or demethylated compounds formed after administration of ketamine hydrochloride are a prerequisite for future clinical investigations and a deeper understanding of the individual role of the isomers of these metabolites. In this study, we present development and validation of a method based on supercritical-fluid chromatography (SFC) coupled to single quadrupole MS detection that allows the separation of ketamine as well as all of its relevant metabolites detected in urine of healthy volunteers. Inherently to SFC methods, the run times of the novel protocol are four times shorter than in a comparable HPLC method, the use of organic solvents is reduced and we were able to demonstrate and validate the successful enantioselective separation and quantification of R- and S-ketamine, R- and S-norketamine, R- and S-dehydronorketamine and (2R,6R)- and (2S,6S)-hydroxynorketamine isomers differing in either constitution, stereochemistry, or both, in one run. The developed method may be useful in investigating the antidepressant efficacy of ketamine in clinical trials.

Nonpolar derivatives of heterocyclic aromatic screening hits like the non-selective sirtuin inhibitor splitomicin tend to be poorly soluble in biological fluids. Unlike sp

Openers of neuronal voltage-gated potassium channels (KV ) are of interest as therapeutic agents for treating pain (flupirtine) and epilepsy (retigabine). In an effort to better understand the mechanisms of action and toxicity of flupirtine, we synthesized nine novel analogues with varying redox behavior. Flupirtine can be oxidatively metabolized into azaquinone diimines; thus, the oxidation potentials of flupirtine and its analogues were measured by cyclic voltammetry. KV 7.2/3 (KCNQ2/3) opening activity was determined by an established assay with HEK293 cells overexpressing these channels. A link was found between the oxidation potentials of the compounds and their EC50 values for potassium channel opening activity. On the other hand, no correlation was observed between oxidation potentials and cytotoxicity in cultures of transgenic mouse hepatocytes (TAMH). These results support the idea that oxidative metabolites of flupirtine contribute to the mechanism of action, similar to what was recently proposed for acetaminophen (paracetamol), but not to hepatotoxicity.

Die akute Herzinsuffizienz ist definiert durch das plotzliche Auftreten von Symptomen einer Herzinsuffizienz, die einer notfallmasigen Therapie bedurfen. Die Krankenhausmortalitat betragt bis zu 10 %, beim kardiogenen Schock sogar 50–70 %. Entscheidend fur eine adaquate Therapie sind das rasche Erkennen der zugrunde liegenden Ursache der akuten Herzinsuffizienz und eine moglichst kausale Therapie. Beim akuten Koronarsyndrom steht daher die Akutkoronarangiographie mit Intervention im Vordergrund. Die medikamentosen und apparativen Therapieprinzipien zielen auf eine Reduzierung klinischer Stauungszeichen, eine Vor- und Nachlastsenkung, eine myokardiale Kontraktilitatsteigerung und die Durchbrechung der neurohumoralen Aktivierung. Bis heute gibt es im Gegensatz zur chronischen Herzinsuffizienz keine medikamentose Therapie, welche die Sterblichkeit senken kann. Von neuen Therapieansatzen ist zumindest eine Symptomverbesserung, das Verhindern von Endorganschaden und im gunstigsten Fall eine Reduktion der kardiovaskularen Ereignis-, Rehospitalisations- und Mortalitatsrate zu fordern.

The layout of multipurpose screening libraries must address criteria for the compounds such as novelty, diversity potential, innovative design, and last but not least synthetic tractability. While academic compound collections are often innovative, novel, and highly divers, synthesis of analogs or larger substance quantities is often hampered by complex multistep syntheses with low overall yields. In addition, covalently binding compounds and interaction motifs designed to bind metal ions were discriminated against by the paradigm that these interaction types must almost inevitably lead to toxic effects. We would like to challenge this hypothesis. The lack of such interactions could be a reason for frequent failure in the disclosure of hits for hitherto undruggable target proteins using commercially available screening collections. Thus, easily synthesizable screening candidates equipped to bind covalently to nucleophiles or to metalloenzymes by chelation are under-represented in public access screening libraries. Within this work, we present the synthesis and deposition of 88 compounds with five distinct functional classes, each of which features under-represented screening motifs, for example, metal ion complexation, reversible covalent binding, or halogen bonding. The collection includes acetohydrazides, acylhydrazones, propylene glycol ethers, 2-cyanoacetamides, and 2-cyanoacrylamides. The rational for the synthesis of most of the compounds was recently published by our group and is now supplemented by additional compounds reported here for the first time. The public access disposition enables academic research groups to collectively expand the druggable space and interdisciplinary collaborate within the scientific field.

Glutathione peroxidases (GPx) were the first selenocysteine enzymes identified. They play critical roles in cellular defense to excess $$\hbox {H}_{2}\hbox {O}_{2}$$ and lipid peroxides, with GPx1 contributing the most cellular activity. In the treatment of cancer, for example, in lymphomas and leukaemias, evidence has been accumulating that up-regulation of the GPx system may serve to protect cancer cells from oxidative stress caused by anticancer drugs. We hypothesize that small molecules which block GPx1 could help overcome acquired resistance to anticancer drugs by raising the level of oxidative stress in cancer cells. Our previous efforts identified an acylhydrazone as a lead structure for the inhibition of GPx1. Now we report the microwave-supported synthesis and inhibitory screening of a series of 78 analogs. The special conformational isomerism resulting of the acylhydrazone functionality was investigated by the analysis of distinct NMR data and crystal structures, indicating that conformers at the C(O)–N hydrazide bond are responsible for this phenomena. Though some of the analogs showed poor aqueous solubility and could not be tested in the enzyme assay, the combinatorial approach led to the identification of a closely related isomer of the lead compound with increased inhibitory activity: $${N'}$$ -[1-(4-hydroxyphenyl)ethylidene]-2-(1H-imidazol-1-yl)acetohydrazide. This success supports the idea that novel GPx1 inhibitors can be developed by drug-design methods and paves the way for a new class of GPx1 inhibitors.

Type 17 helper T (Th17) cells producing the proinflammatory signature cytokine interleukin (IL)-17 are conterregulated by regulatory T cells (Treg) producing anti-inflammatory cytokines like transforming growth factor (TGF)-β and interleukin-(IL)-10. An imbalance of the Th17/Treg-ratio toward Th17 cell subset was shown to be involved in plaque destabilization and acute myocardial infarction (AMI), while no data exist in infarction-related cardiogenic shock (CS). The objective of this study was to evaluate the role of Th17/Treg and their related cytokines in uncomplicated AMI and infarction-related CS.In an observational monocentric study, blood sample from age-matched healthy controls (HC, n = 20), patients with uncomplicated AMI (n = 20), patients with CS who survived for at least 28 days (CS-survivors, n = 20) and CS-non-survivors (n = 20) were analyzed. Circulating Th17 and Treg cell subsets and their intracellular cytokine expression were measured by flow cytometry and associated with circulating proinflammatory Th17-derived cytokines IL-6, IL-17 and their anti-inflammatory Treg-derived cytokines TGF-β and IL-10 measured by enzyme immunoassay. According to the severity of ACS, CS-non-survivors showed the highest levels of Th17 (p 0.001) and the lowest levels of Treg cells (p 0.001) favoring a Th17/Treg imbalance toward the proinflammatory Th17 response (p 0.001). Changes of T cell subsets were also associated with a proinflammatory cytokine expression measured by increased IL-6 (p 0.001) and IL-17 levels (p 0.001) and decreased TGF-β (p 0.001) and IL-10 levels (p = 0.057). For the Th17/Treg-ratio at admission, a cut-off point of0.33 had a sensitivity of 90 % and a specificity of 80 % to determine 28-day mortality in CS (confirmed by ROC analysis, area under the curve: 0.88 ± 0.06, p 0.001). Th17/Treg-ratio0.33 was observed to be an independent predictor for 1-year mortality in CS confirmed by Cox proportional hazard analysis (hazard ratio (HR): 4.31; 95 % confidence interval (CI) 1.44-12.93; p = 0.009).The Th17/Treg imbalance toward a Th17 shift might represent a promising candidate as therapeutic target and risk indicator in cardiogenic shock.

Racemic misonidazole, a radiosensitizer formally used in radiation therapy of cancer and to date still applied, was once reported to exhibit strong inhibitory effects on mouse glutathione peroxidases (GPX). This appeared to qualify misonidazole as a lead structure for the development of novel GPX inhibitors to cause oxidative stress in chemotherapy-resistant tumors. A unique feature of misonidazole as an inhibitor of GPX is the absence of a thiol functionality. Therefore, it was expected to selectively target inhibition devoid of promiscuous interactions with cations and sulfhydryl groups. We synthesized the isomers of misonidazole and analyzed the ability of chiroptical high-performance liquid chromatography (HPLC) to identify the particular enantiomers. Due to the chiral pool synthesis, the assignment of the correct configuration could be verified. Finally, we evaluated both isomers for their inhibitory activities on bovine erythrocyte GPx-1, which is 87% homologous to the human enzyme. Despite the previously reported inhibition of racemic misonidazole on the less homologous mouse GPx-1, we did not find any significant inhibitory activity on the bovine enzyme for either isomer. Though misonidazole appears unlikely to be an inhibitor of human GPx-1 activity, we still spotlight misonidazole as a promising fragment-like lead structure in general.

Aromatic heterocycles with basic nitrogen atoms as well as carboxylic acid derivatives are the dominating chemical space in the universe of drug-like molecules. These established and exceedingly evaluated structural motifs have to be combined with elements of diversity in order to chart less well-explored galaxies of chemical space and to be able to tackle seemingly undruggable targets. Flat scaffolds should be replaced by shapely molecular cores. In this context, it has been unheeded that phenyl rings in diaryl sulfides are less co-planar than in ethers and that the metabolic interconnection of sulfides and sulfoxides offers advantages that are unalike from the chemistry of amines and N-oxides in the CHN-O world. Moreover, σ-hole potentials increase with the polarizability of the atom N < P < O < S and do not only play a role in long-time overlooked halogen bonds. Examples for λ2 , λ4 , and λ6 S-based functionalities related to improved solubility, reduced drug resistance, linkers in drug conjugates, drug-targeting to parasites, and as basis for drug monitoring in sports are given and discussed.

Acute heart failure (AHF) is defined as the rapid onset of, or changes in, the symptoms and signs of heart failure (HF). It is a life-threatening situation in which diagnosis and initiation of therapy are crucial. The treatment aims are to stabilize the patient, improve clinical symptoms, and increase long-term survival rates. Few treatments have been investigated in clinical trials. This review summarizes the principles of pharmacologic treatment, the underlying clinical trials, and new pharmacologic targets.

Starting from cyclopentadiene, two racemic mixtures of 4-aminocyclopentane-1,3-diols were prepared in 8 steps and characterized. Structure determination proved the anticipated trans-orientation of the two oxygen atoms with respect to the plane of the ring. The fragment-like new compounds are small and hydrophilic, devoid of rotatable bonds, and offer stereochemically defined attachment points for substituents. Thus, these platforms for diversity are suitable starting points for the construction of combinatorial libraries of lead-like 4-amidocyclopentane-1,3-diols or natural product analogs. As a proof of concept, cyclopentanoid anandamide analogs were prepared using these molecular platforms and evaluated as tools for the investigation of unresolved issues in the molecular biology of anandamide.

Im Juni 2012 wurden von der Europaischen Gesellschaft fur Kardiologie (ESC) die neuen europaischen Leitlinien zur akuten und chronischen Herzinsuffizienz mit reduzierter sowie erhaltener Ejektionsfraktion vorgestellt. Die Gabe von Mineralokortikoid-Rezeptor-Antagonisten (MRA) ist nun in allen Stadien der unter Betablockade und ACE-Hemmer-Therapie weiterhin symptomatischen chronischen Herzinsuffizienz indiziert. Dies beruht auf den Ergebnissen der EMPHASIS-HF-Studie. Patienten mit Herzinsuffizienz NYHA II–IV, einer EF 70 /min vor dem Hintergrund einer vollstandigen medikamentosen Herzinsuffizienztherapie einschlieslich maximal tolerierter Betablockade, sollten mit dem If-Kanal-Hemmer Ivabradin behandelt werden. Diese Empfehlung basiert auf der SHIFT-Studie und einigen Anschlussanalysen. Die RAFT-Studie begrundete die erweiterte Indikation fur CRT-Systeme bei Patienten im Sinusrhythmus und einer Kammerkomplexbreite von > 130 ms mit Linksschenkelblock-Konfiguration. Im Bereich der akuten Herzinsuffizienz hat die RELAX-AHF-Studie mit dem Derivat des Schwangerschaftshormons Relaxin hoffnungsvolle Ergebnisse gezeigt, die zur Durchfuhrung groser Placebo-kontrollierter Studien mit harten klinischen Endpunkten auffordert. Die nachfolgende Ubersicht befasst sich mit den Innovationen dieser Leitlinien und fasst die zugrundeliegenden Studien zusammen, wobei sie sich auf die chronische systolische und die akute Herzinsuffizienz fokussiert.

Fragment-based lead discovery (FBLD) has evolved from an emerging technology to a state-of-the-art approach in drug research. The efficacious use of fragment libraries for the discovery of hits and generation of lead structures has to an increasing extent become implemented both within academia and the pharmaceutical industry but the careful or optimal selection of appropriate fragments remains a demanding task, especially when fragments are intended for the lead generation in more than one or even diverse and difficult targets.Progress in non-commercial screening collections of fragment-like compounds for multiple screening purposes deposited at academic institutions is reviewed as well as approaches for the generation of slim and shapely novel platforms for diversity. Recent literature on multipurpose fragment screening libraries and the papers presented at the EFMC-ISMC meeting in Berlin in August 2012 have been taken into account.Existing fragment libraries tend to focus on sp (2)-rich compounds covering well-explored areas of chemical space. In order to improve the quality of the hits and to be able to tackle seemingly undruggable targets, flat scaffolds should be replaced by shapely molecular cores dominated by sp (3) hybridization. Structurally novel fragments are needed and in this respect, the role of halogen bonds has been underestimated. Pooling strategies for fragment cocktails must be designed to detect simultaneous binding of weak ligands in close proximity: cooperative binding is too important to rely on chance discoveries.

The definitive treatment of hemodynamically stable patients with pulmonary embolism and echocardiographically proven moderate to severe right ventricular dysfunction is unclear. We discuss the cases of a 45-year-old woman and a 62-year-old man that fulfilled the above criteria, but had a high risk for adverse events. Although both patients were treated according to current guidelines, one underwent successful surgical embolectomy the same day and the other was resuscitated a few days later. Surgery is an alternative for carefully selected patients with mild right ventricular dysfunction, but a high risk for adverse events that would otherwise be treated the same way as low- to moderate-risk patients.

Vascular integrity is disturbed in shock contributing to clinical appearance and serious outcomes. While angiopoietin (Ang)-1 protects from vascular inflammation and leakage, Ang-2 disrupts endothelial barrier function. The imbalance of Ang-1 and Ang-2, their association to haemodynamic deterioration, and their prognostic relevance are not known and, thus, were prospectively evaluated in patients with cardiogenic shock (CS) in this study.Plasma Ang-1 and Ang-2 were determined by the enzyme immunoassay in patients with CS (n = 96), uncomplicated acute myocardial infarction (AMI, n = 20) and age-matched healthy controls (HC, n = 20). Angiopoietin-2 was three-fold elevated in CS compared with HC (P0.001), remained elevated in non-survivors, and decreased in survivors (P0.001). In contrast, Ang-1 decreased up to 35-fold in CS (P0.001). Angiopoietin-1 was correlated and Ang-2 was inversely related to a cardiac power index and mixed venous oxygen saturation, respectively (P0.001 for all). To assess the prognostic relevance, two outcome variables were considered: the 28-day mortality and the survival time (follow-up time 1 year). For Ang-2 at admission a cut-off point of 2500 pg/mL had a sensitivity of 61% and a specificity of 80% to determine 28-day mortality in CS (confirmed by receiver operating characteristic analysis, area under the curve = 0.71 ± 0.06, P0.001). Angiopoietin-2 levels2500 pg/mL at admission were observed to be an independent predictor for 1-year mortality in CS confirmed by Cox proportional hazard analysis [hazard ratio (HR) 2.11; 95% confidence interval (CI) 1.03-4.36; P = 0.042].Circulating Angs are closely related to outcome and severity in CS. Angiopoietin-2 emerged as an independent predictor of 28-day and 1-year mortality in CS. Larger studies are required to define the cut-off and predictive values for Ang-2. Angiopoietins may be prognostic biomarkers for survival in CS and might represent a novel therapeutic target.

As to the alignment of "Horizon 2020", ir is a more integrated approach to European science policy than expressed in the proposals previously drafted, and specifically considers: (i) promoting excellence in Science, (ii) establishing a sound industrial leadership and (iii) expressing an ambition to address current and future societal challenges. In this respect, the quest for a knowledge-based economy in Europe should result in proposals for industrial and employment policies that will consolidate the major European advantages in the biomedical, healthcare and pharmaceutical sectors. Horizon 2020 also provides the possibility of adopting a more flexible and simplified management route to drive European research through innovation, research and development. What should be additionally considered? Unmet medical needs, under pressure from demographic changes, await the generation of new medicines and health technologies which will evolve into a driver for a unified European policy. We believe that this should be focused on harnessing pharmaceutical knowledge for clinical use, as part of a response to accommodate patient needs and economic growth based on a robust, scientific approach. The bolder ambition for European research is to unlock key bottlenecks currently undermining European competitiveness. The historical lack of an appropriate business/innovation environment with reduced access to adequate risk finance instruments has severed the path for economic growth and industrial development. These issues are of critical importance and a solution is urgently needed to foster translation from the university to the healthcare sector through the generation and support of start-ups, spin-offs, university-industry consortia, and other platforms, which support translational research. The ultimate goal is implementation of holistic programmes: the 'bench to bedside' paradigm of medicines and other healthcare products. The European Research Council supports the basic biomedical research programmes of long term importance for development of medicines; however, fundamental research initiatives on medicines development will not be competitive in such an environment. In order to strengthen the long term outlook, we must foster innovative research within the university sector, EUFEPS proposes that a fund for such research be set up within Horizon 2020, which would be open for individual research groups and which would include Public-Public Partnerships (complementing already existing Public-Private Partnerships). How do we look for implementation? There is an established research agenda for medicines research that is globally focused, and which incorporates a cooperative model between universities and industry, facilitating integration of complex technologies. Regulatory Science will play an important role in this integration. This agenda uses tools arising from systems approaches (including discovery with systems biology and also systems pharmacology) and has the potential for providing better knowledge management, as well as technological innovation (including manufacturing). It also addresses the drive towards personalised medicines and can, with support from both public and private sectors, foster translation of knowledge to new technologies and from that, to new medicinal products and complex integrated systems. This is a part of a strategy capable of solving unmet medical needs, which would increase the quality of life of patients suffering from chronic and debilitating diseases. The instruments to allow the development of a research agenda should strengthen existing partnerships such as the IMI-JU model; allow for the creation of European-network infrastructures that can bring together existing competences with adequate European coordination, thus promoting advanced training and continuous professional development for the pharmaceutical sciences. This will be the cornerstone of a knowledge management strategy, providing education and training for healthcare professionals and scientists. A key role for EUFEPS is to help the research community to embrace these new holistic policies applied to the spectrum of pharmaceutical, medical and cognate sciences.

Ketamine (KET) is a widely used anesthetic drug which is metabolized by CYP450 enzymes to norketamine (n-KET), dehydronorketamine (DHNK), hydroxynorketamine (HNK) and hydroxyketamine (HK). Ketamine is a chiral compound and S-ketamine is known to be the more potent enantiomer. Here, we present the development and validation of three LC-MS/MS assays; the first for the quantification of racemic KET, n-KET and DHNK in human serum, urine and feces; the second for the separation and quantification of the S- and R-enantiomers of KET, n-KET and DHNK, and the third for separation and quantification of 2S,6S-hydroxynorketamine (2S,6S-HNK) and 2R,6R-hydroxynorketamine (2R,6R-HNK) in serum and urine with the ability to separate and detect 10 additional hydroxylated norketamine metabolites of racemic ketamine. Sample preparation was done by liquid-liquid extraction using methyl tert-butyl ether. For achiral determination of KET and its metabolites, an isocratic elution with ammonium acetate (pH 3.8; 5mM) and acetonitrile on a C18 column was performed. For the separation of S- and R-enantiomers of KET, n-KET and DHNK, a gradient elution was applied using a mobile phase of ammonium acetate (pH 7.5; 10mM) and isopropanol on the CHIRAL-AGP® column. The enantioselective separation of the HNK metabolites was done on the chiral column Lux®-Amylose-2 with a gradient method using ammonium acetate (pH 9; 5mM) and a mixture of isopropanol and acetonitrile (4:1). The mass spectrometric detection monitored for each analyte 2-3 mass/charge transitions. D4-ketamine and D4-n-KET were used as internal standards. The assays were successfully validated according to current bioanalytical guidelines and applied to a pilot study in one healthy volunteer. Compared to previously published methods, our assays have superior analytical features such as a lower amount of required matrix, faster sample preparation, shorter analytical run time and higher sensitivity (LLOQ up to 0.1ng/ml). Moreover, our assay enables for the first time the enantioselective determination of 2R,6R- and 2S,6S-HNK which were shown to be responsible for the promising antidepressant effects of ketamine.

Together forever? Functional selection was applied to finally achieve separation of the analgesic properties of opiods from serious side effects such as potentially lethal respiratory depression. A Gi-biased μ-opioid-receptor agonist (PZM21) was identified that stabilizes previously unexplored receptor conformations. This compound relieves pain in mice without causing hypoventilation or addiction.

Using a smartphone touchscreen to control apps mirrored to a distant display is hard, since the user cannot see where she is touching while looking at the distant screen. Tactile landmarks at the back of the phone can mitigate this problem, especially in landscape mode [3]: By moving a finger across these landmarks, the user can haptically estimate the finger position in proportion to the touchscreen. Upon pinching the thumb resting above the touchscreen towards that finger at the back, the finger position is transferred to the front and registered as a touch. However, despite proprioception, this technique leads to a shift between back and front position, denoted as pinch error. We investigated this error using different target locations, device thicknesses, and tilt angles to derive target sizes that can be acquired at a 96% success rate.

A 23-year old female patient is referred to our intensive care unit from another hospital because of progredient neurological deterioration with sopor. One week before, she had experienced non-specific pain in her upper right stomach combined with vomitus and nausea. For two days, she had been treated with ciprofloxacin 2 × 500 mg / d by her primary care physician. Except for appendectomy in childhood, no other diseases were reported. Clinical investigation: Physical examination reveals mild scleral and dermal jaundice. There is tenderness of the upper right abdomen. Initially, no neurological pathological findings are obvious. Laboratory results show an increase of liver aminotransferases, bilirubin, and ammonia. The toxicological screening is negative.Hepatic encephalopathy due to acute hepatic failure is diagnosed and detoxification of ammonia with lactulose is started. Transiugular liver biopsy confirms lobular hepatitis with cytolysis. Because of progressive deterioration additional treatment to prevent cerebral oedema is initiated. Consecutively serum osmolality decreases, and ammonia and neurological status normalize.This report illustrates toxic acute liver failure after treatment with ciprofloxacin.

Tetrazoles are small functional heterocycles that are suited to serve simultaneously as aromatic platform for diversity and as functional interaction motif. Furthermore, the tetrazole ring and its deprotonated tetrazolate counterpart are metal ion complexing ligands that possess a rich variety of binding and bridging modes. We recently demonstrated that fragments containing the tetrazole moiety and a metal chelating hydrazide group are well suited to discover selective screening hits with high ligand efficiency for a given protein target. Here, we report the synthesis and characterization of new polydentate tetrazole-containing screening compounds and their synthetic precursors as well as their deposition in a multipurpose screening library in the frame of the EU-OPENSCREEN network. The pure and well-characterized screening compounds could be useful to aid drug discovery programs for multiple or hitherto undruggable targets by enclosure of under-represented tetrazole derivatives.

Carrier aggregation (CA) is considered to be the key-enabler for LTE-Advanced (LTE-A) allowing data rates up to the Gbit/s range. Besides advanced semiconductor and acoustic technologies, CA requires tailored circuits. This paper presents co-design of a Bulk Acoustic Wave (BAW) CA quadplexer (QPX), a GaAs power amplifier (PA) and the necessary matching in between them for obtaining optimum RF front-end module performance for CA needs. One of the most challenging CA cases is covered: Band 1-Band 3. We will discuss antenna matching, isolation in all involved bands and transmit (Tx) matching for high output power and efficiency. Module measurements show state-of-the-art performance. Furthermore, measurements and simulations are in excellent agreement from DC up to 8 GHz with a dynamic range of 90 dB.

Anamnese und klinischer Befund: Eine 21-jahrige Patientin wurde wegen zunehmender Vigilanzminderung stationar aufgenommen. Anfangs standen agitiert-delirante Symptome, spater Somnolenz und Sopor im Vordergrund. Vorausgegangen war ein grippaler Infekt mit Fieber, Kopfschmerzen, Ubelkeit und Erbrechen, der uber mehrere Tage mit Acetylsalicylsaure behandelt worden war. Vorerkrankungen waren nicht bekannt. Untersuchungen: Die korperliche und klinisch-neurologischen Untersuchungen ergaben auser der Vigilanzminderung keinen auffalligen Befund. Das EEG zeigte mittelschwere Allgemeinveranderungen. Die kranielle MR-Tomographie und die Liquorpunktion waren unauffallig. Laborchemisch zeigte sich ein deutlicher Anstieg der Transaminasen sowie eine Hyperammonamie. Das toxikologische Screening war unauffallig. Therapie und Verlauf: Es wurde die Diagnose einer hepatischen Enzephalopathie infolge akuten Leberversagens gestellt und sofort eine Ammoniakdetoxikation mit Laktulose eingeleitet. Die transjugulare Leberbiopsie ergab den Befund einer massiven Leberverfettung, deren Ursache weder serologisch noch histologisch geklart werden konnte. Bei progredienter Vigilanzminderung wurde die Patientin intubiert und invasiv beatmet. Trotz raschen Absinkens des Ammoniak-Spiegels kam es zu einer weiteren neurologischen Verschlechterung. Im Kontroll-CCT zeigte sich ein Hirnodem mit Zeichen einer beginnenden Einklemmung. Eine Hirnodemtherapie wurde eingeleitet. Die Patientin starb infolge eines sekundaren Hirnodems bei hepatischer Enzephalopathie. Folgerung: Bei Symptomen einer hepatischen Enzephalopathie bei akuter fettiger Leberdegeneration nach einem grippalen Infekt sowie der fakultativen Einnahme von Acetylsalicylsaure muss nach Ausschluss haufiger Ursachen eines akuten Leberversagens differenzialdiagnostisch das seltene Reye-Syndrom diskutiert werden.

Despite their simplicity, relatively few examples of 1,2,4 (1,3,4)-amino-, azido-, and hydroxy-substituted cyclopentanes are reported in the literature. We found that cyclopent-3-en-1-ol can be transformed into a significant variety of compounds of this class by relatively common and efficient synthetic procedures. Stereochemical control of epoxidation of the cyclopentene double bond can be achieved by varying the substitutents at C4. The C4 substituent and epoxide functional group can be converted into a variety of intermediates with differential protection designed for use in applications requiring regiospecific control for further elaboration of the cyclopentane scaffold.

Die akute Herzinsuffizienz bedarf einer raschen Diagnose und wenn moglich einer kausalen Therapie, um die Entwicklung eines kardiogenen Schocks zu vermeiden. Die medikamentosen Therapieprinzipien zielen auf eine Abnahme von klinischen Stauungszeichen, eine Vor- und Nachlastsenkung, eine myokardiale Kontraktilitatsteigerung und die Durchbrechung der neurohumoralen Aktivierung. Dabei soll die klinische Symptomatik verbessert, das Auftreten von Endorganschaden verhindert sowie wenn moglich die kardiovaskulare Ereignis-, Rehospitalisations- und Mortalitatsrate reduziert werden. Eine kombinierte diuretische und / oder vasodilatatorische Standardtherapie ist einer Monotherapie im Hinblick auf die Organprotektion uberlegen. Positiv inotrope und vasoaktive Substanzen sollten nur bei Hypotonie mit Zeichen der Kreislaufzentralisation eingesetzt werden. Sie verbessern die Hamodynamik und die Organperfusion unter Inkaufnahme einer Ubersterblichkeit durch proarrhythmogene Effekte. Daher sollten sie so niedrig wie moglich dosiert und so rasch wie moglich ausgeschlichen werden. Eine vorbestehende Beta-Blocker-Therapie sollte, sofern keine hamodynamische Instabilitat besteht, fortgesetzt werden. Wichtig ist, dass alle herzinsuffizienten Patienten vor Entlassung erneut leitliniengetreu auf Beta-Blocker und ACE-Hemmer eingestellt werden, da dadurch Rehospitalisation und Mortalitat gesenkt werden konnen. Von neuen medikamentosen Therapieansatzen ist zumindest eine Symptomverbesserung und im gunstigsten Fall eine Reduktion von Rehospitalisation und Mortalitat zu fordern.

Activation of the receptor for advanced glycation end products by its ligands promotes inflammatory processes and tissue injury. The available evidence suggests that soluble forms of receptor for advanced glycation end products circulating in the plasma may neutralize the ligand-mediated damage by acting as a decoy. Thus, it is hypothesized that receptor for advanced glycation end products expression might be deleterious, whereas soluble receptor for advanced glycation end products might be beneficial in cardiogenic shock. However, until now, no data exist regarding the role of soluble receptor for advanced glycation end products and receptor for advanced glycation end products in humans with cardiogenic shock complicating myocardial infarction.Prospective observational cohort study.Intensive critical care unit of a university hospital.Forty patients with cardiogenic shock complicating acute myocardial infarction, 20 age-matched patients with acute uncomplicated myocardial infarction and, 20 age-matched healthy volunteers.None.Monocytic receptor for advanced glycation end products expression assessed by flow cytometry was significantly increased in cardiogenic shock nonsurvivors (137.02±7.48 mean fluorescence intensity; n=13) compared to survivors (67.80±8.33 mean fluorescence intensity; n=17; p.001). Conversely, nonsurvivors had significantly decreased plasma soluble receptor for advanced glycation end products levels (79.87±10.62 arbitrary units; n=13; p=.004) compared to survivors (127.65±10.52 arbitrary units; n=17) as assessed by Western blotting. Receptor for advanced glycation end products expression and soluble receptor for advanced glycation end products levels were determined as independent predictors for 28-day mortality in cardiogenic shock confirmed by receiver-operator characteristics and multivariate analysis (receptor for advanced glycation end products: area under the curve, 0.943±0.05; p.001; soluble receptor for advanced glycation end products: area under the curve, 0.815±0.08; p.01). Both receptor for advanced glycation end products103.6 mean fluorescence intensity or soluble receptor for advanced glycation end products76.88 arbitrary units independently predicted a 27.87-fold (p.001) and a 3.97-fold (p=.019) increase in 28-day mortality in cardiogenic shock.Enhanced monocytic receptor for advanced glycation end products expression and decreased plasma soluble receptor for advanced glycation end products levels play a central role in patients with cardiogenic shock associated with proinflammatory and destroying pathways, resulting in an enhanced 28-day mortality-rate. Receptor for advanced glycation end products and soluble receptor for advanced glycation end products may be prognostic biomarkers for survival in cardiogenic shock and might represent a novel therapeutic target in cardiogenic shock.

Aims To investigate the role of Toll-like receptor 2 (TLR2) in uncomplicated acute myocardial infarction (AMI) and in cardiogenic shock (CS). Methods and results In patients with uncomplicated AMI ( n = 20), CS ( n = 30) and in age-matched healthy controls (HC; n = 20), TLR2 expression on monocytes was assessed by flow cytometry. Tumour necrosis factor alpha (TNFα) and interleukin-6 (IL6) expression in monocytes was analysed by intracellular cytokine staining. TLR2 expression was increased in patients with AMI compared with HC [mean fluorescence intensity (MFI) 111.1 ± 8.2 vs. 66.9 ± 1.5, P < 0.001]. In patients with CS, TLR2 expression was further increased (132.8 ± 5.6 MFI, P = 0.009 vs. AMI). This was accompanied by an increased expression of the proinflammatory cytokines TNFα (4.3 ± 1.6% in AMI vs. 20.5 ± 5.9% in CS, P = 0.004) and IL6 (6.3 ± 1.6% in AMI vs. 20.6 ± 6.2% in CS, P = 0.032). Furthermore, in all patients with myocardial infarction (AMI + CS; n = 50), a strong correlation between the monocytic TLR2 expression and the symptom to reperfusion time ( r 2= 0.706, P < 0.001) was found, implying tissue hypoxia dependency. Symptom to reperfusion time is a main factor to influence TLR2 expression but not the presence of CS. TLR2 expression of mononuclear cells exposed in vitro to hypoxia was assessed by flow cytometry and western blot. In vitro measurements showed a hypoxia-mediated monocytic TLR2 expression up-regulation. Conclusion We demonstrate TLR2 up-regulation and increased proinflammatory cytokine expression in circulating monocytes in AMI/CS depending on disease severity, implying an important role of TLR2 expression in ischaemic injury.

CD4(+)CD28(null) cells represent an aggressive and long-living T cell subpopulation, capable of infiltrating atheromatous plaque, leading to destabilisation and resulting in acute coronary syndromes (ACS). The aim of this study was to evaluate whether statins decrease the number of circulating CD4(+)CD28(null) T cells by apoptosis in patients with ACS.Patients with troponin-positive ACS (n = 35) without cholesterol lowering drugs were randomised to placebo (n = 17) or rosuvastatin 20 mg (n = 18) once daily for 6 weeks. CD4(+)CD28(null) T cell abundance (1%) was distributed equally among the two groups at entry (n = 10 per group). Within 72 h rosuvastatin treatment significantly reduced mean CD4(+)CD28(null) T cell numbers (37 × 10⁶/L vs. placebo 122 × 10⁶/L, n = 20, P = 0.041), IFN-γ production (62.6 vs. 101.5%, P = 0.049) and increased apoptosis of these T cells (63.4 vs. 12.3%, P0.001). The intrinsic mitochondria-dependent pathway measured by the anti-apoptotic protein expression of B cell lymphoma 2 (BCL-2) was significantly down-regulated (mean fluorescence intensity 16.08 vs. placebo 43.34, P0.001).The down-regulation of anti-apoptotic BCL-2 expression by statins induces apoptosis in CD4(+)CD28(null) T cells. Targeting CD4(+)CD28(null) T cells in ACS statins could provide one further therapeutic strategy to prevent acute life-threatening coronary events.

NO-Donatoren haben aufgrund ihrer hamodynamischen Wirkungen positive Effekte bei Patienten mit Herzinsuffizienz. Zur Therapie der akuten Herzinsuffizienz sind Glyceroltrinitrat, Isosorbiddinitrat und Natrium-Nitroprussid etabliert. Sie fuhren durch eine Reduktion der Vor- und Nachlast zu einer Stabilisierung des Patienten. Aufgrund der Toleranzentwicklung eignen sich NO-Donatoren nur eingeschrankt zur Langzeittherapie. Bei der Behandlung der chronischen Herzinsuffizienz wird aktuell nur eine Kombinationstherapie aus Isosorbiddinitrat und Hydralazin in besonderen Situationen empfohlen. Das Nitrat Pentaerythrityltetranitrat nimmt aufgrund einer verminderten Toleranzentwicklung eine besondere Stellung ein. Die Wirkung dieses Medikaments bei Patienten mit chronischer Herzinsuffizienz und sekundarer pulmonaler Hypertonie wird aktuell in klinischen Studien untersucht.

History A 32-year-old, very slightly overweight woman (body mass index of 25) without any cardiovascular risk factors presented with acute chest pain. She reported taking the appetite suppressant sibutramine daily for three months. She was not pregnant and did not remember episodes of serious mental stress or infection during the last few weeks. Physical examination was unsuspicious. Investigation Laboratory results revealed an elevation of serum markers of myocardial ischemia. The electrocardiogram showed ST segment depressions and T wave inversions in leads II, III and aVF, indicating a nontransmural inferior myocardial infarction. Treatment and course Coronary angiography showed patent coronary arteries with inferior wall hypokinesia. There were no signs of a coronary dissection. Assuming that the acute coronary syndrome had been induced by coronary spasms, the patient was treated with amlodipine and ramipril. Conclusion It seemed reasonable to suspect that the intake of sibutramine had induced coronary spasms. However, this is a diagnosis of exclusion. Three case reports have previously been published about acute myocardial infarctions, possibly related to sibutramin intake, in young patients with a negligible cardiovascular risk profile. The European Medicines Agency has questioned the marketing authorisations for sibutramine (January 2010). In patients presenting with acute coronary syndromes which can not be clearly related to cardiovascular risk factors, it is crucial to obtain a complete drug history. Some patients might continue to take sibutramine.

(2R,3S,4R,5R)-5-(6-Amino-9H-purin-9-yl)-3-hydroxy-4-[2-(methylamino)benzamido]tetrahydrofuran-2-yl-methoxy[(hydroxy)phosphoryloxy][(hydroxy)phosphoryl]dichloromethylphosphonic acid was synthesized as a chemically and metabolically stable analog of ATP substituted with a fluorescent methylanthranoyl (MANT) residue. The compound is intended for studying the binding site and function of adenylyl cyclases (ACs), which was exemplified by studying its interaction with Bacillus anthracis edema factor (EF) AC exotoxin.

The involvement of purine salvage in the accumulation of current trypanocidal drugs is important for the treatment of African sleeping sickness. The substrate specificity of essential nucleoside transporters is therefore of physiological and pharmacological interest. With the intention to contribute to the knowledge in the field, a series of 16 adenosine derivatives with substituents in N(6)-position were prepared in order to evaluate their potential to inhibit Trypanosoma brucei spp. in vitro. An unmodified ribose moiety was selected to conserve key molecular recognition motifs of the arsenal of integral membrane proteins expressed in large numbers on the protozoan plasma membrane. Two of the new compounds prepared using a polymer-assisted acylation protocol showed antitrypanosomal activities in the single digit micromolar concentration range.

Acute hypertensive emergencies occur in 5 to 35 % of the patients in perioperative care. This is associated with an increase in perioperative complications: the rate of bleedings, myocardial infarctions, cerebral ischemia and overall mortality is increased 4-fold. Before an operation, it is of utmost importance to recognize predictors for hypertensive emergencies and to achieve an adequate blood pressure control. There has so far been no agreement on a blood pressure threshold at which blood pressure needs to be reduced. Antihypertensive therapy is a bedside decision of the responsible physician. It aims at a rapid decrease of hypertensive peaks without risking a reduced organ perfusion. The optimal drug for the treating hypertensive emergencies should have a rapid and safe action. Antihypertensives of first choice are esmolol, metoprolol, urapidil or clonidin. The oral therapy with nifedipine or nitrendipine has the risk of abrupt hypotensive episodes and should therefore only be administered after exclusion of an acute coronary syndrome or cardiac failure Because of its toxicity sodium nitroprusside is an antihypertensive drug of second choice. Nitrates or diuretics are supplementary drugs for patients with angina pectoris, cardiac failure or renal insufficiency. Newer substances (fenoldopam, nicardipine, clevidipine) have promising kinetic properties but are not as yet been approved for antihypertensive treatment in Germany.

Given the more or less global spread of multidrug-resistant plasmodia, structurally diverse starting points for the development of chemotherapeutic agents for the treatment of malaria are urgently needed. Thus, a series of 20 adenosine derivatives with a large lipophilic substituent in N 6 -position were prepared in order to evaluate their potential to inhibit the chloroquine resistant Plasmodium falciparum strain K1 in vitro. The rationale for synthesis of these structures was the high probability of interactions with multiple adenosine associated targets and the assumption that a large hydrophobic N 6 -(4-phenoxy)benzyl substitution should allow the molecules to diffuse across parasite membranes. Starting from readily available inosine, the new compounds were prepared as single isomers using a polymer-assisted acylation protocol enabling the straightforward isolation of the target compounds in pure form. Heterocyclic ring systems were synthesized on-bead on Kenner’s safety-catch linker prior to acylation of the scaffold in solution. Most of the highly pure compounds displayed anti-plasmodial activity in the low micromolar or even submicromolar concentration range.

The conversion of 1-deoxy-D-xylulose-5-phosphate (DOXP) to 2-C-methyl-D-erythritol-4-phosphate (MEP) is effectively blocked by 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) inhibitors such as the natural antibiotic fosmidomycin. Prediction of binding affinities for closely related Dxr ligands as well as estimation of the affinities of structurally more distinct inhibitors within this class of non-hydrolyzable phosphate mimics relies on the synthesis of fosmidomycin derivatives with a broad range of target affinity. Maintaining the phosphonic acid moiety, linear modifications of the lead structure were carried out in an effort to expand the SAR of this physicochemically challenging class of compounds. Synthetic access to a set of phosphonic acids with inhibitory activity (IC(50)) in the range from 1 to >30 microM vs. E. coli Dxr and 0.4 to 20 microM against P. falciparum Dxr is reported.

Endothelial progenitor cells (EPC) predict morbidity and mortality in patients at cardiovascular risk.Patients with low EPC counts and impaired endothelial colony forming activity have a higher incidence for cardiovascular events compared to patients with high EPC counts and favorable colony forming activity. The pathophysiological basis for this finding may be an insufficient endothelial cell repair by EPC.We postulate that EPC influence coronary endothelial function which itself is relevant for the outcome of patients at cardiovascular risk. To test this hypothesis in humans, endothelial function was invasively assessed in 90 patients with coronary heart disease by quantitative coronary angiography during intracoronary acetylcholine infusion. Flow cytometry of mononuclear cells isolated from peripheral blood was performed to assess CD133(+) or CD34(+)/KDR(+) EPC. EPC function was assessed ex vivo by determination of endothelial colony forming units. Low EPC number as well as impaired endothelial colony forming activity correlated with severely impaired coronary endothelial function in univariate analysis. Multivariate analysis revealed that only the number of EPC predicts severe endothelial dysfunction independent of classical cardiovascular risk factors. Endothelial function closely correlates with the number of circulating EPC providing new mechanistic insights and options for risk assessment in patients with coronary heart disease.

The parallel acylation of N-{3-[4-(3-aminopropyl)piperazin-1-yl]propyl}-7-chloroquinolin-4-amine with polymer-bound carboxylic acids opened straightforward access to novel aminoquinolines with activity against Plasmodium falciparum strains in vitro. Using this amino scaffold prepared in solution and polymer-bound carboxylic, we have synthesized a series of 29 new compounds in good to excellent yield and purity. Biological evaluation included determination of the activity against a chloroquine (CQ) sensitive strain and a CQ resistant mutant. Most of the novel structures presented here displayed activity against both strains in the lower nanomolar range, four compounds showed an at least fourfold increase in the ratio of inhibition of CQ resistant to sensitive strains over CQ itself. These results suggest that this derivatization technique is a useful method to speed up structure-activity relationship studies on aminoquinolines toward improved activity versus CQ resistant strains of P. falciparum in vitro.

Angiopoietin-2 (Ang-2) is a mediator of capillary leakage, and increased Ang-2 levels were associated with poor in-hospital outcome in a pilot study in cardiogenic shock (CS). In this larger study, we followed this hypothesis and aimed at assessing the predictive role of Ang-2 on short- and long-term mortality, investigating the effect of intra-aortic balloon pump (IABP) treatment on Ang-2 levels, and identifying clinical and procedural predictors of increased Ang-2.In the IABP-SHOCK II-trial, 600 patients with CS complicating acute myocardial infarction were assigned to therapy with or without IABP. This substudy included 189 randomized patients with serial blood sampling performed at days 1, 2, and 3. No significant differences in Ang-2 levels were found between patients with or without IABP. The Ang-2 levels above the median at day 1 were associated with 30-day [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.26-3.10, P = 0.002) and 1-year mortality (HR 2.21, 95% CI 1.49-3.27, P0.001). Stratification of patients according to Ang-2 levels at day 3 increased these associations (30 days HR 5.15, 95% CI 2.80-9.45, P0.001; 1 year HR 5.24, 95% CI 3.19-8.58, P0.001). The Ang-2 concentrations were independent predictors for mortality in multivariate analysis (30 days HR 4.82, 95% CI 1.52-15.23, P = 0.007; 1 year HR 2.01, 95%CI 1.24-3.24, P = 0.005). Predictors of increased Ang-2 levels at day 3 were baseline Ang-2, development of acute kidney injury, bleeding events or transfusion, and impaired reperfusion.In CS, high levels of Ang-2 are independently associated with poor short- and long-term outcome and associated with the reperfusion success as well as complications.URL: www.clinicaltrials.gov; unique identifier: NCT00491036.

Patients with cardiogenic shock have a very high mortality. Here we report the first use of a percutaneous pulsatile cardiac assist device, based on a diagonal pump synchronized with the heart cycle by means of an electrocardiographic signal in adult pigs. Eight domestic pigs underwent mandatory ventilation. During sinus rhythm, there were no differences between pulsatile and nonpulsatile perfusion with regard to pulmonary artery pressure, pulmonary wedge pressure, central venous pressure, mean arterial pressure (MAP), mean pulse pressure, and mean coronary artery flow (CAF). After 2 min of complete cardiac arrest (ventricular fibrillation), circulatory support with the i-cor in venoarterial nonpulsatile extracorporeal membrane oxygenation (ECMO) mode (3 L/min) restored systemic circulation, with an increase of MAP to 78.3 mm Hg and CAF to 5.27 mL/min. After changing from ECMO settings to pulsatile mode (3 L/min, 75 bpm, pulse amplitude range 3500 rpm), MAP did not change significantly (75.6 mm Hg); however, CAF increased to 8.45 mL/min. After changing back to nonpulsatile mode, MAP remained stable (83.6 mm Hg), but CAF decreased to 4.85 mL/min. Thereafter, pulsatile cardiac assist was established with a reduced blood flow of 2.5 L/min, and the pulse amplitude range was extended to 4500 rpm. Under these conditions, MAP remained stable (71.0 mm Hg), but CAF significantly increased to 15.2 mL/min (P 0.05). Percutaneous cardiac support using a venoarterial cardiac assist device equipped with a novel diagonal pump is able to restore and increase systemic and coronary circulation during ventricular fibrillation. Electrocardiographically triggered synchronized cardiac assist provides an additional increase of coronary artery flow. These promising results are to be confirmed in humans.

Introduction Cardiogenic shock (CS) is the leading cause of death in patients hospitalized with acute myocardial infarction (AMI). Biomarkers might help in risk stratification and understanding of pathophysiology. Preliminary data suggests that patients with CS face a profound increase in the osteocyte-derived hormone fibroblast growth factor 23 (FGF-23), which acts as a negative regulator of serum phosphate levels. The present study aimed to assess the predictive role of FGF-23 for clinical outcome in a large cohort of CS patients with and without renal dysfunction. Methods In the randomized Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial, 600 patients with CS complicating AMI were assigned to therapy with or without IABP. Our predefined biomarker substudy included 182 patients. Blood sampling was performed in a standardized procedure at three different time points (day 1 (day of admission), day 2 and day 3). Differences in outcome of patients with FGF-23 levels median were compared by log-rank testing. Stepwise logistic regression modeling was performed to identify predictors of death at 30 days and Cox regression analysis for time to death during the first year. Results At all three time points, nonsurvivors had significantly higher FGF-23 levels compared to survivors (P

Krisenhafte Blutdruckanstiege werden an internistischen Notaufnahmen in bis zu 25% der Falle beobachtet. Dabei handelt es sich zu etwa 75% um eine hypertensive Gefahrensituation („urgency“) und bei etwa 25% um einen hypertensiven Notfall („emergency“). Bezogen auf die Gesamtbevolkerung sind hypertensive Notfalle jedoch selten (weniger als 1% der behandelten Hypertoniker). Gehen Blutdruckkrisen mit akuten kardialen, vaskularen oder zerebralen Organschadigungen einher, liegt ein hypertensiver Notfall („emergency“) vor, der eine umgehende Blutdrucksenkung erfordert. Dabei hangt die Intensitat der Blutdrucksenkung von der Art der Endorganschadigung ab: kardiale und vaskulare Endorganschaden bedurfen einer raschen Blutdrucksenkung und -normalisierung, wohingegen zerebrale Endorganschaden nach Beseitigung der Blutdruckspitzen eher von leicht erhohten/hochnormalen Blutdruckwerten profitieren. Bei einer hypertensiven Dringlichkeit („urgency“) liegen keine Endorganschaden vor, hier reicht eine langsame Absenkung des arteriellen Blutdrucks.

We have applied a fast and high-yielding method for the parallel amidation of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-butylamine yielding analogs of the partial dopamine receptor agonist BP 897. Using this amino scaffold prepared in solution and polymer-bound carboxylic acid equivalents, we have synthesized a series of high affinity dopamine D(3) receptor ligands. The novel compounds were obtained in good to excellent yield and purity. Biological evaluation included determination of binding affinities at hD(2S) and hD(3) receptor subtypes. From the 22 novel structures presented here, compound 4v showed high affinity (K(i) (hD(3)) 1.6nM) and a 136-fold preference for the D(3) receptor versus that for the D(2) receptor subtype. Our results suggest that this derivatization technique is a useful method to speed up structure-activity relationships studies on dopamine receptor subtype modulators.

A red azo-dye, 4-(4-sulfamoylphenylazo)benzoic acid, is suggested as an alternative for the Kenner safety-catch linker. The deeply coloured molecule allows for naked-eye bead-property estimation with regard to loading level and linker integrity without affecting the functionality of the safety-catch linker. A practical synthesis of the title compound is reported.

In 1971 Kenner et al. introduced the safety-catch principle into solid phase peptide synthesis. Thus two contradicting needs were addressed. On the one hand, sufficient stability of the linker substrate bond to impede hydrolysis or similar side reactions, on the other hand mild chemical conditions allowing for unscathed liberation of the precious products. Over the years this linker type emerged in several different chemical disciplines and nowadays it presents a useful and broadly applicable tool. Recent advancements and applications based on Kenner's safety-catch linker are reviewed.