Article
Pharmacology & Pharmacy
Cajsa Aranaes, Sebastian Blid Skoeldheden, Elisabet Jerlhag
Summary: Preclinical studies have identified potential medications, such as GLP-1R agonists, varenicline, and bupropion, for the treatment of AUD. Combining different medications is a recent approach, but there is limited research on the combination of semaglutide with varenicline or bupropion for AUD. Another approach is to combine medication with feeding interventions, but the effects of combining high fat diet with semaglutide on alcohol drinking are unknown.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Md Ashraf-Uz-Zaman, Guangchen Ji, Dalton Tidwell, Linda Yin, Smathorn Thakolwiboon, Jie Pan, Riley Junell, Zach Griffin, Sadisna Shahi, Derek Barthels, Md Sanaullah Sajib, Paul C. Trippier, Constantinos M. Mikelis, Hiranmoy Das, Mirla Avila, Volker Neugebauer, Nadezhda A. German
Summary: The dopaminergic system plays a crucial role in regulating immune responses and pharmacological modulation of dopamine system activity is thought to be therapeutically relevant for conditions like Parkinson's disease and multiple sclerosis. Restoration of dopamine levels may inhibit neuroinflammation and new dopamine transporter inhibitors have shown potential anti-inflammatory effects and benefits in animal models mimicking MS.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Chemistry, Medicinal
Kuo Hao Lee, Andrew D. Fant, Jiqing Guo, Andy Guan, Joslyn Jung, Mary Kudaibergenova, Williams E. Miranda, Therese Ku, Jianjing Cao, Soren Wacker, Henry J. Duff, Amy Hauck Newman, Sergei Y. Noskov, Lei Shi
Summary: This study established a screening platform for DAT and hERG binding, using machine learning, experimental validation, and molecular modeling. Results show that robust QSAR models can be developed, with predictive power on specific functional states of a protein.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Biochemistry & Molecular Biology
Ingrid Fatima Zattoni, Thales Kronenberger, Diogo Henrique Kita, Lais Danciguer Guanaes, Matheus Murmel Guimaraes, Larissa de Oliveira Prado, Melanie Ziasch, Luis C. Vesga, Fabiane Gomes de Moraes Rego, Geraldo Picheth, Marcos Brown Goncalves, Miguel D. Noseda, Diogo R. B. Ducatti, Antti Poso, Robert W. Robey, Suresh Ambudkar, Vivian Rotuno Moure, Alan Guilherme Goncalves, Glaucio Valdameri
Summary: A newly discovered porphyrin derivative (4B) was identified as an inhibitor of the ABCG2 transporter, capable of overcoming multidrug resistance in vitro and showing selective inhibition towards ABCG2 without being transported by it.
CHEMICO-BIOLOGICAL INTERACTIONS
(2022)
Article
Multidisciplinary Sciences
Biao Qiu, Doreen Matthies, Eva Fortea, Zhiheng Yu, Olga Boudker
Summary: The study reveals the structure and operation mechanism of hEAAT3, suggesting it operates by an elevator mechanism involving three functionally independent subunits. The substrate-binding site near the cytoplasm has remarkably low affinity for the substrate, facilitating rapid substrate release and transport turnover. The mechanism of coupled uptake of sodium ions and substrate is conserved across evolutionarily distant families, augmented by coupling to protons in EAATs, and a mechanism involving a conserved glutamate residue mediates proton symport.
Article
Biology
Zachary J. Frangos, Katie A. Wilson, Heather M. Aitken, Ryan Cantwell Chater, Robert J. Vandenberg, Megan L. O'Mara
Summary: This study investigates the binding of cholesterol to GlyT2 protein, its modulation of glycine transport rate, and its influence on the inhibition of GlyT2 by bioactive lipids. The results show that the recruitment of membrane cholesterol to a binding site formed by transmembrane helices 1, 5, and 7 modulates the inhibition of glycine transport. The synergy between cholesterol and allosteric inhibitors provides a novel mechanism for the development of alternative therapeutics for neuropathic pain and other SLC6 transporters.
LIFE SCIENCE ALLIANCE
(2023)
Article
Biochemistry & Molecular Biology
Marta Baczewska, Elzbieta Supruniuk, Klaudia Bojczuk, Pawel Guzik, Patrycja Milewska, Katarzyna Kononczuk, Jakub Dobroch, Adrian Chabowski, Pawel Knapp
Summary: The study aimed to assess the dominant energy substrate transport mechanism in ovarian cancer cells and predict clinical outcomes using genomic aberrations. The researchers found differential gene expression in high-grade serous carcinoma and suggested the potential use of glucose and lactate transport as therapeutic targets to impede ovarian cancer growth.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Dakota B. Zinani, Hanna N. Wetzel, Andrew B. Norman
Summary: This study revealed significant differences in the intake rate, satiety threshold, and half-life of different DAT inhibitors in rats. The duration of lever-pressing following termination of drug access was correlated with the t(1/2) estimates, suggesting a relationship between the time needed for animals to stop lever pressing and the PK properties of the agonist.
Article
Biochemistry & Molecular Biology
Iva Spreitzer, Josefin Keife, Tobias Strasser, Predrag Kalaba, Jana Lubec, Winfried Neuhaus, Gert Lubec, Thierry Langer, Judith Wackerlig, Irena Loryan
Summary: This study compared the tissue distribution and metabolism of S-CE-123 and R-modafinil, two dopamine transporter inhibitors, with a focus on their distribution in the central nervous system. The findings revealed distinct differences between the two compounds, with S-CE-123 demonstrating superior transport across the blood-brain barrier and blood-spinal cord barrier. In terms of cellular membrane transport, S-CE-123 primarily localized in the brain interstitial space, while R-modafinil distributed more evenly. Additionally, S-CE-123 showed significantly faster hepatic metabolism compared to R-modafinil. These findings suggest that S-CE-123 has potential as a candidate for the treatment of cognitive decline.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biology
Dino Luethi, Julian Maier, Deborah Rudin, Daniel Szollosi, Thomas J. F. Angenoorth, Stevan Stankovic, Matthias Schittmayer, Isabella Burger, Jae-Won Yang, Kathrin Jaentsch, Marion Holy, Anand Kant Das, Mario Brameshuber, Gisela Andrea Camacho-Hernandez, Andrea Casiraghi, Amy Hauck Newman, Oliver Kudlacek, Ruth Birner-Gruenberger, Thomas Stockner, Gerhard J. Schutz, Harald H. Sitte
Summary: This study investigates the subunit stoichiometry and function of the plasmalemmal norepinephrine transporter (NET), showing the direct regulation of NET organization and function by phosphatidylinositol 4,5-bisphosphate (PIP2).
COMMUNICATIONS BIOLOGY
(2022)
Article
Biology
Alison L. Kearney, Dougall M. Norris, Milad Ghomlaghi, Martin Kin Lok Wong, Sean J. Humphrey, Luke Carroll, Guang Yang, Kristen C. Cooke, Pengyi Yang, Thomas A. Geddes, Sungyoung Shin, Daniel J. Fazakerley, Lan K. Nguyen, David E. James, James G. Burchfield
Summary: The study reveals that Akt phosphorylates IRS1 and IRS2, engaging in a negative feedback mechanism that limits the synthesis of PIP3 and plasma membrane-associated PI3K. This phosphorylation leads to the depletion of IRS1/2 from the plasma membrane, reducing their interaction with the insulin receptor.
Article
Biophysics
Matthew C. Chan, Balaji Selvam, Heather J. Young, Erik Procko, Diwakar Shukla
Summary: This study investigated the structural dynamics of human SERT to various intermediate states and elucidated the complete substrate import pathway. The transition from the occluded to inward-facing state was found to be the rate-limiting step for substrate import, and the substrate decreased the free energy barriers for achieving the inward-facing state.
BIOPHYSICAL JOURNAL
(2022)
Article
Cell Biology
Dongmei Mai, Rongqing Chen, Ji Wang, Jiawei Zheng, Xiuping Zhang, Shaogang Qu
Summary: This study investigated the role of 14 crucial amino acid residues in TM2 of EAAT2, finding that mutations in these residues affect the localization, substrate affinity, and activity of EAAT2, thereby influencing its transporter function.
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
(2021)
Article
Biology
Huseyin Ilgu, Jean-Marc Jeckelmann, David Kalbermatter, Zohre Ucurum, Thomas Lemmin, Dimitrios Fotiadis
Summary: The structure of the L-arginine/agmatine transporter AdiC was determined at high resolution, revealing the importance of water molecules in stabilizing the protein and shaping substrate-binding sites. Molecular dynamics simulations highlighted the crucial role of water molecules in protein stability and function, as well as their importance as placeholders for substrate atoms.
Article
Chemistry, Medicinal
Julien Graff, Jennifer Mueller, Anna Sadurni, Matthias Rubin, Ines Andre Canivete Cuissa, Claudia Keller, Marco Hartmann, Simon Singer, Jurg Gertsch, Karl-Heinz Altmann
Summary: A series of derivatives of the substrate amino acid l-tryptophan have been investigated for inhibition of the L-type amino acid transporter LAT1. The 5-substituted derivative showed the highest potency, while the replacement of the carboxy group led to a complete loss in potency. Increasing the steric bulk at the 5-position did not improve the inhibitory activity. None of these derivatives were found to be substrates for LAT1-mediated transport.
Article
Biochemistry & Molecular Biology
Felix P. Mayer, Marco Niello, Daniela Cintulova, Spyridon Sideromenos, Julian Maier, Yang Li, Simon Bulling, Oliver Kudlacek, Klaus Schicker, Hideki Iwamoto, Fei Deng, Jinxia Wan, Marion Holy, Rania Katamish, Walter Sandtner, Yulong Li, Daniela D. Pollak, Randy D. Blakely, Marko D. Mihovilovic, Michael H. Baumann, Harald H. Sitte
Summary: Increasing extracellular levels of serotonin can ameliorate symptoms of depression and anxiety-related disorders. The study found that certain ring-substituted cathinones show preference for the release of serotonin and exert 5-HT-associated effects in behavioral models. These compounds have low abuse liability and potential for adverse events.
MOLECULAR PSYCHIATRY
(2023)
Article
Multidisciplinary Sciences
Marco Niello, Spyridon Sideromenos, Ralph Gradisch, Ronan O'Shea, Jakob Schwazer, Julian Maier, Nina Kastner, Walter Sandtner, Kathrin Jantsch, Carl R. Lupica, Alexander F. Hoffman, Gert Lubec, Claus J. Loland, Thomas Stockner, Daniela D. Pollak, Michael H. Baumann, Harald H. Sitte
Summary: By using various in vitro, computational, and in vivo approaches, we found that the drug-binding kinetics of S-enantiomers of pyrovalerone analogs at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, the slow dissociation (i.e., slow koff) of S-enantiomers of pyrovalerone analogs from DAT can predict their more persistent in vivo effects compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT in determining the in vivo profile of effects produced by psychostimulant drugs.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Basavraj Khanppnavar, Julian Maier, Freja Herborg, Ralph Gradisch, Erika Lazzarin, Dino Luethi, Jae-Won Yang, Chao Qi, Marion Holy, Kathrin Jaentsch, Oliver Kudlacek, Klaus Schicker, Thomas Werge, Ulrik Gether, Thomas Stockner, Volodymyr M. Korkhov, Harald H. Sitte
Summary: This study reports the structure of human organic cation transporter 3 (OCT3) and provides insight into its inhibition by two specific inhibitors, decynium-22 and corticosterone. Understanding OCT3 polymorphisms is important, and this research sheds light on their impact.
NATURE COMMUNICATIONS
(2022)
Editorial Material
Psychiatry
Felix P. Mayer, Dino Luethi, Lorena B. Areal, Harald H. Sitte
FRONTIERS IN PSYCHIATRY
(2023)
Article
Cell Biology
Thomas J. F. Angenoorth, Julian Maier, Stevan Stankovic, Shreyas Bhat, Sonja Sucic, Michael Freissmuth, Harald H. Sitte, Jae-Won Yang
Summary: Organic cation transporters (OCTs) are membrane proteins that uptake monoamines, cationic drugs and xenobiotics. In this study, the researchers investigated two potentially misfolded variants of organic cation transporter 3 (OCT3) and found that pre-treatment with the chemical chaperone 4-PBA led to increased membrane expression and transport capacity of the misfolded variants. This study provides proof of principle that folding-deficient SLC22 transporter variants, especially OCT3, can be rescued by chaperones.
Article
Biology
Dino Luethi, Julian Maier, Deborah Rudin, Daniel Szollosi, Thomas J. F. Angenoorth, Stevan Stankovic, Matthias Schittmayer, Isabella Burger, Jae-Won Yang, Kathrin Jaentsch, Marion Holy, Anand Kant Das, Mario Brameshuber, Gisela Andrea Camacho-Hernandez, Andrea Casiraghi, Amy Hauck Newman, Oliver Kudlacek, Ruth Birner-Gruenberger, Thomas Stockner, Gerhard J. Schutz, Harald H. Sitte
Summary: This study investigates the subunit stoichiometry and function of the plasmalemmal norepinephrine transporter (NET), showing the direct regulation of NET organization and function by phosphatidylinositol 4,5-bisphosphate (PIP2).
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
N. J. Clauss, F. P. Mayer, W. A. Owens, M. Vitela, K. M. Clarke, M. A. Bowman, R. E. Horton, D. Gruendemann, D. Schmid, M. Holy, G. G. Gould, W. Koek, H. H. Sitte, L. C. Daws
Summary: Concurrent cocaine and alcohol use is a dangerous drug combination that increases extracellular monoamines. Ethanol's ability to inhibit monoamine uptake is dependent on the organic cation transporter 3 (OCT3), while cocaine blocks DAT, NET, and SERT. These findings suggest OCT3 as a potential target for therapeutic intervention in ethanol and ethanol/cocaine use disorders.
MOLECULAR PSYCHIATRY
(2023)
Article
Medicine, General & Internal
Michael Eigenschink, Luise Bellach, Sebastian Leonard, Tom Eric Dablander, Julian Maier, Fabian Dablander, Harald H. Sitte
Summary: This study investigates the popularity, usage, and perceived scientific support of Traditional Chinese Medicine (TCM) in Austria. It found that TCM is widely known and used by a substantial proportion of the population, but there is a disparity between the public perception of TCM as scientific and evidence-based studies. It emphasizes the importance of distributing unbiased, science-driven information.
Article
Biology
Zsuzsanna Gyongy, Gabor Mocsar, Eva Hegedus, Thomas Stockner, Zsuzsanna Ritter, Laszlo Homolya, Anita Schamberger, Tamas Orban, Judit Remenyik, Gergely Szakacs, Katalin Goda
Summary: This study presents methods for simultaneously investigating substrate and nucleotide binding by ABCG2 in cells. The switch from the inward-facing to the outward-facing conformation of ABCG2 is induced by nucleotide binding and facilitated by substrates, while hindered by the inhibitor Ko143. The high-to-low affinity switch of the drug binding site coincides with the transition from the inward-facing to the outward-facing conformation.
Article
Psychiatry
Jacqueline D. Keighron, Jordi Bonaventura, Yang Li, Jae-Won Yang, Emily M. M. DeMarco, Melinda Hersey, Jianjing Cao, Walter Sandtner, Michael Michaelides, Harald H. H. Sitte, Amy Hauck Newman, Gianluigi Tanda
Summary: Typical and atypical dopamine uptake inhibitors (DUIs) have different effects on behavior, neurochemistry, and addiction potential due to their preference for distinct conformations of the dopamine transporter (DAT) to form ligand-transporter complexes. Cocaine and typical psychostimulants reduce dopamine clearance rate, but only typical DUIs stimulate evoked dopamine release, unrelated to DAT affinity. Pretreatment with a CaMKII alpha inhibitor blunts the stimulatory effects of cocaine on dopamine release, suggesting a role for this kinase in modulating cocaine's effects. Atypical DUIs blunt cocaine's effects, indicating a unique mechanism underlying their potential as medications for psychostimulant use disorder.
TRANSLATIONAL PSYCHIATRY
(2023)
Review
Physiology
Manan Bhatt, Laure Gauthier-Manuel, Erika Lazzarin, Rocco Zerlotti, Christine Ziegler, Andre Bazzone, Thomas Stockner, Elena Bossi
Summary: γ-Aminobutyric acid (GABA) acts as the primary inhibitory neurotransmitter in the CNS, regulated by GABA transporters (GATs). Although GAT1 has been extensively studied, the roles of other GABA transporters, especially BGT-1, remain unclear. This review aims to compare GAT1 and BGT-1, leveraging the knowledge of GAT1 to shed light on the unanswered questions regarding BGT-1.
FRONTIERS IN PHYSIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Francesca R. Brugnoli, Marion Holy, Marco Niello, Julian Maier, Marcus Hanreich, Mario Menzel, Matthias Haberler, Niklas Zulus, Thomas Pickl, Christa Ivanova, Lisa D. Muiznieks, Benjamin Garlan, Harald H. Sitte
Summary: To address the drawbacks of current techniques in studying the interaction of monoamine transporters, researchers developed an automated microfluidic platform for more accurate and standardized cell-based assays. The platform successfully validated the effects of control compounds such as D-Amphetamine, GBR12909, p-chloroamphetamine, and paroxetine on the two transporters.
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
(2023)
Article
Chemistry, Medicinal
Kornel Ozvoldik, Thomas Stockner, Elmar Krieger
Summary: The transition from 3D glasses to VR headsets in the industry has brought challenges for modelers. However, a novel software implementation using a VR headset at a desk has been introduced, providing a relaxing and immersive workplace. This software, called YASARA Model, combines VR functionality with a molecular graphics engine and offers additional features and interactive tutorials.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Neurosciences
Felix P. Mayer, Marco Niello, Simon Bulling, Yuan-Wei Zhang, Yang Li, Oliver Kudlacek, Marion Holy, Fatemeh Kooti, Walter Sandtner, Gary Rudnick, Diethart Schmid, Harald H. Sitte
Summary: This study provides further insights into the pharmacology of mephedrone at hDAT and hSERT. It was found that mephedrone induces carrier-mediated release via hDAT and hSERT and is sensitive to protein kinase C inhibitor. Additionally, mephedrone displays greater efficacy as a releaser at hSERT than at hDAT, indicating its higher activity at hSERT.