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Design, Synthesis, and Biological Evaluation of 4,4'-Difluorobenzhydrol Carbamates as Selective M1 Antagonists

Jonas Kilian, Marius Ozenil, Marlon Millard, Dorka Fürtös, Verena Maisetschläger, Wolfgang Holzer, Wolfgang Wadsak, Marcus Hacker, Thierry Langer, Verena Pichler
2022 Pharmaceuticals  
Due to their important role in mediating a broad range of physiological functions, muscarinic acetylcholine receptors (mAChRs) have been a promising target for therapeutic and diagnostic applications alike; however, the list of truly subtype-selective ligands is scarce. Within this work, we have identified a series of twelve 4,4'-difluorobenzhydrol carbamates through a rigorous docking campaign leveraging commercially available amine databases. After synthesis, these compounds have been
more » ... d for their physico–chemical property profiles, including characteristics such as HPLC-logD, tPSA, logBB, and logPS. For all the synthesized carbamates, these characteristics indicate the potential for BBB permeation. In competitive radioligand binding experiments using Chinese hamster ovary cell membranes expressing the individual human mAChR subtype hM1-hM5, the most promising compound 2 displayed a high binding affinitiy towards hM1R (1.2 nM) while exhibiting modest-to-excellent selectivity versus the hM2-5R (4–189-fold). All 12 compounds were shown to act in an antagonistic fashion towards hM1R using a dose-dependent calcium mobilization assay. The structural eligibility for radiolabeling and their pharmacological and physico–chemical property profiles render compounds 2, 5, and 7 promising candidates for future position emission tomography (PET) tracer development.
doi:10.3390/ph15020248 pmid:35215360 pmcid:PMC8879200 fatcat:embw3p3pvzdotehtukct3fcahi

Update on PET Tracer Development for Muscarinic Acetylcholine Receptors

Marius Ozenil, Jonas Aronow, Marlon Millard, Thierry Langer, Wolfgang Wadsak, Marcus Hacker, Verena Pichler
2021 Pharmaceuticals  
The muscarinic cholinergic system regulates peripheral and central nervous system functions, and, thus, their potential as a therapeutic target for several neurodegenerative diseases is undoubted. A clinically applicable positron emission tomography (PET) tracer would facilitate the monitoring of disease progression, elucidate the role of muscarinic acetylcholine receptors (mAChR) in disease development and would aid to clarify the diverse natural functions of mAChR regulation throughout the
more » ... vous system, which still are largely unresolved. Still, no mAChR PET tracer has yet found broad clinical application, which demands mAChR tracers with improved imaging properties. This paper reviews strategies of mAChR PET tracer design and summarizes the binding properties and preclinical evaluation of recent mAChR tracer candidates. Furthermore, this work identifies the current major challenges in mAChR PET tracer development and provides a perspective on future developments in this area of research.
doi:10.3390/ph14060530 pmid:34199622 pmcid:PMC8229778 fatcat:ec5itvibdfblplrcloppuhtjcq

Learning induces coordinated neuronal plasticity of metabolic demands and functional brain networks [article]

Sebastian Klug, Godber M Godbersen, Lucas Rischka, Wolfgang Wadsak, Verena Pichler, Manfred Kloebl, Marcus Hacker, Rupert Lanzenberger, Andreas Hahn
2021 bioRxiv   pre-print
Information for Learning induces coordinated neuronal plasticity of metabolic demands and functional brain networks Sebastian Klug 1# , Godber M Godbersen 1# , Lucas Rischka 1 , Wolfgang Wadsak 2,3 , Verena  ... 
doi:10.1101/2021.11.12.468351 fatcat:xb3mzc7elrd2rasxxpiqy22slm

Development and evaluation of a rapid analysis for HEPES determination in 68Ga-radiotracers

Sarah Pfaff, Tina Nehring, Verena Pichler, Jens Cardinale, Markus Mitterhauser, Marcus Hacker, Wolfgang Wadsak
2018 EJNMMI Research  
HEPES is a favorable buffer for 68Ga-complexations in radiochemical laboratories. The drawback of this buffer is its prescribed limit of 200 μg per recommended application volume in the final formulation. Currently, a TLC test according to the European Pharmacopoeia (Ph. Eur.) has to be performed for quantification, but this analysis suffers from low reliability and reproducibility and is based on a subjective, semi-quantitative visual evaluation. In this study, the TLC method according to the
more » ... h. Eur. and two literature-known HPLC assays for HEPES quantification were evaluated. Additionally, the development of an improved TLC method was performed. The assay according to Antunes et al. provided a reasonable quantification of HEPES using HPLC. Additionally, a reliable and conclusive TLC method was developed, which facilitates quantitative analysis by means of a pixel-based evaluation. A comparison of those two methods with the Ph. Eur. TLC assay pinpoints the superiority of the HPLC as well as the new TLC assay. Furthermore, evaluation of HEPES contents using both TLC assays by 28 subjects supported the conclusion that the newly developed TLC method is clearly favorable. The TLC method according to the Ph. Eur. provides unsatisfactory results in terms of conclusiveness and reproducibility. In contrast, a reported HPLC assay showed valid results, with the drawback of high technical effort. An optimized alternative is provided by the improved TLC method described in this work that results in reliable outcomes and additionally offers quantitative analysis.
doi:10.1186/s13550-018-0449-6 pmid:30353250 pmcid:PMC6199202 fatcat:yklra5k7tnhlvohtccyn7mdgwy

Pitfalls and solutions of the fully-automated radiosynthesis of [11C]metoclopramide

Verena Pichler, Marius Ozenil, Karsten Bamminger, Chrysoula Vraka, Marcus Hacker, Oliver Langer, Wolfgang Wadsak
2019 EJNMMI Radiopharmacy and Chemistry  
Pichler et al. EJNMMI Radiopharmacy and Chemistry (2019) 4:31 Page 11 of 14 Pichler et al. EJNMMI Radiopharmacy and Chemistry (2019) 4:31 Page 3 of 14 Pichler et al.  ...  EJNMMI Radiopharmacy and Chemistry (2019) 4:31 Page 5 of 14 Pichler et al. EJNMMI Radiopharmacy and Chemistry(2019) 4:31  ... 
doi:10.1186/s41181-019-0083-2 pmid:31853677 pmcid:PMC6920278 fatcat:udbicbt5tbfwrcucutie67q7zi

The soil microbial food web revisited: Predatory myxobacteria as keystone taxa?

Sebastian Petters, Verena Groß, Andrea Söllinger, Michelle Pichler, Anne Reinhard, Mia Maria Bengtsson, Tim Urich
2021 The ISME Journal  
AbstractTrophic interactions are crucial for carbon cycling in food webs. Traditionally, eukaryotic micropredators are considered the major micropredators of bacteria in soils, although bacteria like myxobacteria and Bdellovibrio are also known bacterivores. Until recently, it was impossible to assess the abundance of prokaryotes and eukaryotes in soil food webs simultaneously. Using metatranscriptomic three-domain community profiling we identified pro- and eukaryotic micropredators in 11
more » ... an mineral and organic soils from different climes. Myxobacteria comprised 1.5–9.7% of all obtained SSU rRNA transcripts and more than 60% of all identified potential bacterivores in most soils. The name-giving and well-characterized predatory bacteria affiliated with the Myxococcaceae were barely present, while Haliangiaceae and Polyangiaceae dominated. In predation assays, representatives of the latter showed prey spectra as broad as the Myxococcaceae. 18S rRNA transcripts from eukaryotic micropredators, like amoeba and nematodes, were generally less abundant than myxobacterial 16S rRNA transcripts, especially in mineral soils. Although SSU rRNA does not directly reflect organismic abundance, our findings indicate that myxobacteria could be keystone taxa in the soil microbial food web, with potential impact on prokaryotic community composition. Further, they suggest an overlooked, yet ecologically relevant food web module, independent of eukaryotic micropredators and subject to separate environmental and evolutionary pressures.
doi:10.1038/s41396-021-00958-2 pmid:33746204 pmcid:PMC8397742 fatcat:jxkz5gp7zvge5j7b7tra7vsioq

Tumor-Targeting of EGFR Inhibitors by Hypoxia-Mediated Activation

Claudia Karnthaler-Benbakka, Diana Groza, Kushtrim Kryeziu, Verena Pichler, Alexander Roller, Walter Berger, Petra Heffeter, Christian R. Kowol
2014 Angewandte Chemie International Edition  
The development of receptor tyrosine-kinase inhibitors (TKIs) was a major step forward in cancer treatment. However, the therapy with TKIs is limited by strong side effects and drug resistance. The aim of this study was the design of novel epidermal growth factor receptor (EGFR) inhibitors that are specifically activated in malignant tissue. Thus, a Co III -based prodrug strategy for the targeted release of an EGFR inhibitor triggered by hypoxia in the solid tumor was used. New inhibitors with
more » ... helating moieties were prepared and tested for their EGFR-inhibitory potential. The most promising candidate was coupled to Co III and the biological activity tested in cell culture. Indeed, hypoxic activation and subsequent EGFR inhibition was proven. Finally, the compound was tested in vivo, also revealing potent anticancer activity.
doi:10.1002/anie.201403936 pmid:25079700 pmcid:PMC4336855 fatcat:pcv2fz2ayrfh7ehjtqak4zs3mu

Sex differences in monetary reward and punishment processing are associated with fast dynamics of dopamine synthesis [article]

Andreas Hahn, Murray B Reed, Verena Pichler, Paul Michenthaler, Lucas Rischka, Godber M Godbersen, Wolfgang Wadsak, Marcus Hacker, Rupert Lanzenberger
2019 bioRxiv   pre-print
Women and men show different behavioral sensitivity to reward and punishment, however, in humans the underlying neurotransmitter action has not yet been identified. Based on functional PET, we introduce a novel approach to enable the investigation of rapid changes in dopamine neurotransmission during cognitive task performance. In men, monetary gain induced 78% increase in dopamine synthesis vs. 49% for loss, whereas women showed the reverse pattern. Behavioral modeling revealed a direct
more » ... tion of task-specific dopamine synthesis with reward sensitivity in men and punishment sensitivity in women. Since dopaminergic sex differences were not reflected in BOLD signal changes, we emphasize a careful interpretation of fMRI-based studies on reward. This may have important implications in psychiatric conditions with sex-specific prevalence rates, alterations in reward processing and dopamine signaling. The high temporal resolution and magnitude of task-specific changes make fPET a promising tool to investigate such neurotransmitter dynamics in health and disease.
doi:10.1101/2019.12.23.886812 fatcat:5t4lfkwscnhntg6gccajvblh2m

Synthesis, Biological, and Computational Evaluation of Antagonistic, Chiral Hydrobenzoin Esters of Arecaidine Targeting mAChR M1

Marius Ozenil, Jonas Aronow, Daniela Piljak, Chrysoula Vraka, Wolfgang Holzer, Helmut Spreitzer, Wolfgang Wadsak, Marcus Hacker, Verena Pichler
2020 Pharmaceuticals  
Muscarinic acetylcholine receptors (mAChRs) are a pivotal constituent of the central and peripheral nervous system. Yet, therapeutic and diagnostic applications thereof are hampered by the lack of subtype selective ligands. Within this work, we synthesized and chemically characterized three different stereoisomers of hydrobenzoin esters of arecaidine by NMR, HR-MS, chiral chromatography, and HPLC-logP. All compounds are structurally eligible for carbon-11 labeling and show appropriate stability
more » ... in Dulbecco's phosphate-buffered saline (DPBS) and F12 cell culture medium. A competitive radioligand binding assay on Chinese hamster ovary cell membranes comprising the human mAChR subtypes M1-M5 showed the highest orthosteric binding affinity for subtype M1 and a strong influence of stereochemistry on binding affinity, which corresponds to in silico molecular docking experiments. Ki values toward M1 were determined as 99 ± 19 nM, 800 ± 200 nM, and 380 ± 90 nM for the (R,R)-, (S,S)-, and racemic (R,S)-stereoisomer, respectively, highlighting the importance of stereochemical variations in mAChR ligand development. All three stereoisomers were shown to act as antagonists toward mAChR M1 using a Fluo-4 calcium efflux assay. With respect to future positron emission tomography (PET) tracer development, the (R,R)-isomer appears especially promising as a lead structure due to its highest subtype selectivity and lowest Ki value.
doi:10.3390/ph13120437 pmid:33266067 fatcat:7nemj2xvh5frxfsyvnn6dayspe

Reconfiguration of functional brain networks and metabolic cost converge during task performance

Andreas Hahn, Michael Breakspear, Lucas Rischka, Wolfgang Wadsak, Godber M Godbersen, Verena Pichler, Paul Michenthaler, Thomas Vanicek, Marcus Hacker, Siegfried Kasper, Rupert Lanzenberger, Luca Cocchi
2020 eLife  
The ability to solve cognitive tasks depends upon adaptive changes in the organization of whole-brain functional networks. However, the link between task-induced network reconfigurations and their underlying energy demands is poorly understood. We address this by multimodal network analyses integrating functional and molecular neuroimaging acquired concurrently during a complex cognitive task. Task engagement elicited a marked increase in the association between glucose consumption and
more » ... l brain network reorganization. This convergence between metabolic and neural processes was specific to feedforward connections linking the visual and dorsal attention networks, in accordance with task requirements of visuo-spatial reasoning. Further increases in cognitive load above initial task engagement did not affect the relationship between metabolism and network reorganization but only modulated existing interactions. Our findings show how the upregulation of key computational mechanisms to support cognitive performance unveils the complex, interdependent changes in neural metabolism and neuro-vascular responses.
doi:10.7554/elife.52443 fatcat:vmxqsonivvhrnpzr6cqmrhu7xa

Chylothorax in thyroid surgery: a very rare case and systematic review of the literature

Verena Merki, Juliane Pichler, Roland Giger, Georgios Mantokoudis
2016 Journal of Otolaryngology - Head and Neck Surgery  
Chylothorax is a very rare but major complication in thyroid surgery and should be apparent to clinicians in this field. Case presentation: We report a case with chylothrax after thyroid surgery in our department that drew our attention. Methods: Systematic review of the literature to evaluate the incidence and the contributing factors of chylothorax after thyroid surgery. Database (PubMed) and hand searches to identify patients with thyroid surgery and postoperative chylothorax. Keywords
more » ... ed chylothorax, thyroidectomy, thyroid surgery and complications. Two independent reviewers screened studies against inclusion and exclusion criteria. Patient characteristics, risk factors, symptoms, treatments and etiopathogenesis were investigated. Results: We identified 13 articles in the literature describing 19 patients with chylothorax after thyroidectomy and described our own case. Ninety percent of the patients underwent thyroidectomy for thyroid cancer. Sixteen patients (80%) underwent thyroidectomy with at least a left lateral neck dissection, 2 patients (10%) underwent thyroidectomy with sternotomy, and in the remaining 2 patients (10%), thyroidectomy with lateral neck dissection on both sides was performed with partial sternotomy. Our calculated incidence for chylothorax with total thyroidectomy and neck dissection was 1.85%; for a thoracic approach the calculated incidence was 7.3%. Conclusions: There are no reports of chylothorax after thyroidectomy without at least a left lateral neck dissection due to advanced thyroid cancer and/or sternotomy due to the thyroid size. The extension of thyroid surgery seems to be the main risk factor in developing chylothorax either through direct surgical trauma or through increased intraductal pressure after thoracic duct ligation. An early diagnosis of chylothorax may avoid severe metabolic or cardiopulmonary complications.
doi:10.1186/s40463-016-0166-y pmid:27756377 pmcid:PMC5070362 fatcat:6pbpiro2cvcmbfqdsncmyy6vbm

Spinophilin expression determines cellular growth, cancer stemness and 5-flourouracil resistance in colorectal cancer

Anna Lena Ress, Verena Stiegelbauer, Daniela Schwarzenbacher, Alexander Deutsch, Samantha Perakis, Hui Ling, Cristina Ivan, George Adrian Calin, Beate Rinner, Armin Gerger, Martin Pichler
2014 OncoTarget  
Pichler is supported by an Erwin-Schroedinger Scholarship of the Austrian Science Funds (project no. J3389-B23).  ... 
doi:10.18632/oncotarget.2329 pmid:25261368 pmcid:PMC4226699 fatcat:snke2f4opbanlm6rkvhqwva3bm

MicroRNAs Associated with Von Hippel–Lindau Pathway in Renal Cell Carcinoma: A Comprehensive Review

Lisa-Maria Schanza, Maximilian Seles, Michael Stotz, Johannes Fosselteder, Georg Hutterer, Martin Pichler, Verena Stiegelbauer
2017 International Journal of Molecular Sciences  
Renal cell carcinoma (RCC) are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the understanding of RCC biology, surgical treatments, and targeted and immuno-therapies in the metastatic setting, the prognosis for advanced RCC patients remains poor. One of the major problems with RCC treatment strategies is inherent or acquired
more » ... sistance towards therapeutic agents over time. The discovery of microRNAs (miRNAs), a class of small, non-coding, single-stranded RNAs that play a crucial role in post-transcriptional regulation, has added new dimensions to the development of novel diagnostic and treatment tools. Because of an association between Von Hippel-Lindau (VHL) genes with chromosomal loss in 3p25-26 and clear cell RCC, miRNAs have attracted considerable scientific interest over the last years. The loss of VHL function leads to constitutional activation of the hypoxia inducible factor (HIF) pathway and to consequent expression of numerous angiogenic and carcinogenic factors. Since miRNAs represent key players of carcinogenesis, tumor cell invasion, angiogenesis, as well as in development of metastases in RCC, they might serve as potential therapeutic targets. Several miRNAs are already known to be dysregulated in RCC and have been linked to biological processes involved in tumor angiogenesis and response to anti-cancer therapies. This review summarizes the role of different miRNAs in RCC angiogenesis and their association with the VHL gene, highlighting their potential role as novel drug targets.
doi:10.3390/ijms18112495 pmid:29165391 pmcid:PMC5713461 fatcat:45scsyr2und43gwzbx5ms3qrxm

Synthesis, Biological Evaluation, and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs

Jonas Kilian, Marlon Millard, Marius Ozenil, Dominik Krause, Khadija Ghaderi, Wolfgang Holzer, Ernst Urban, Helmut Spreitzer, Wolfgang Wadsak, Marcus Hacker, Thierry Langer, Verena Pichler
2022 Molecules  
The muscarinic acetylcholine receptor family is a highly sought-after target in drug and molecular imaging discovery efforts aimed at neurological disorders. Hampered by the structural similarity of the five subtypes' orthosteric binding pockets, these efforts largely failed to deliver subtype-selective ligands. Building on our recent successes with arecaidine-derived ligands targeting M1, herein we report the synthesis of a related series of 11 hydroxylated arecaidine esters. Their
more » ... cal property profiles, expressed in terms of their computationally calculated CNS MPO scores and HPLC-logD values, point towards blood–brain barrier permeability. By means of a competitive radioligand binding assay, the binding affinity values towards each of the individual human mAChR subtypes hM1–hM5 were determined. The most promising compound of this series 17b was shown to have a binding constant towards hM1 in the single-digit nanomolar region (5.5 nM). Similar to our previously reported arecaidine-derived esters, the entire series was shown to act as hM1R antagonists in a calcium flux assay. Overall, this study greatly expanded our understanding of this recurring scaffolds' structure–activity relationship and will guide the development towards highly selective mAChRs ligands.
doi:10.3390/molecules27103173 pmid:35630651 pmcid:PMC9145622 fatcat:2gsqef2ux5eithqelqk5itf53q

Development and Validation of Liquid Chromatography-Based Methods to Assess the Lipophilicity of Cytotoxic Platinum(IV) Complexes

Matthias Klose, Sarah Theiner, Hristo Varbanov, Doris Hoefer, Verena Pichler, Markus Galanski, Samuel Meier-Menches, Bernhard Keppler
2018 Inorganics  
Lipophilicity is a crucial parameter for drug discovery, usually determined by the logarithmic partition coefficient (Log P) between octanol and water. However, the available detection methods have restricted the widespread use of the partition coefficient in inorganic medicinal chemistry, and recent investigations have shifted towards chromatographic lipophilicity parameters, frequently without a conversion to derive Log P. As high-performance liquid chromatography (HPLC) instruments are
more » ... y available to research groups, a HPLC-based method is presented and validated to derive the partition coefficient of a set of 19 structurally diverse and cytotoxic platinum(IV) complexes exhibiting a dynamic range of at least four orders of magnitude. The chromatographic lipophilicity parameters φ0 and Log kw were experimentally determined for the same set of compounds, and a correlation was obtained that allows interconversion between the two lipophilicity scales, which was applied to an additional set of 34 platinum(IV) drug candidates. Thereby, a φ0 = 58 corresponds to Log P = 0. The same approaches were successfully evaluated to determine the distribution coefficient (Log D) of five ionisable platinum(IV) compounds to sample pH-dependent effects on the lipophilicity. This study provides straight-forward HPLC-based methods to determine the lipophilicity of cytotoxic platinum(IV) complexes in the form of Log P and φ0 that can be interconverted and easily expanded to other metal-based compound classes.
doi:10.3390/inorganics6040130 fatcat:l6qcqasr7nh7rd2egtdoeagzem
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