Article
Chemistry, Organic
Felien Reniers, Stijn Anthonissen, Luc Van Meervelt, Wim Dehaen
Summary: This study presents a three-step synthetic pathway for the synthesis of fully decorated 8-azapurines, with a special focus on 6-alkyl derivatives. A diverse library of 8-azapurines was successfully obtained through interrupted CuAAC, oxidation, and cyclization reactions using various alkynes, azides, and amidines. Additionally, postfunctionalization reactions were demonstrated for selected substrates.
Article
Multidisciplinary Sciences
Quanxia Lyu, Shu Gong, Jarmon G. Lees, Jialiang Yin, Lim Wei Yap, Anne M. Kong, Qianqian Shi, Runfang Fu, Qiang Zhu, Ash Dyer, Jennifer M. Dyson, Shiang Y. Lim, Wenlong Cheng
Summary: This study presents a method using a soft resistive force-sensing diaphragm to monitor the contraction forces and beating patterns of cardiac organoids in real-time. The method overcomes the mismatch between the topological complexity and soft tissue properties of organoids and rigid force sensors, providing a new approach for studying the mechanical properties of cardiac tissues.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Rebecca L. Lowery, Monique S. Mendes, Brandon T. Sanders, Allison J. Murphy, Brendan S. Whitelaw, Cassandra E. Lamantia, Ania K. Majewska
Summary: While microglia play a critical role in synaptic plasticity, their utilization of molecular signals varies temporally and regionally. The purinergic receptor P2Y12 is not universally required for synaptic plasticity, but its loss can lead to functional defects in recognition, social memory, and anxiety-like behaviors in adult mice. This highlights the complexity of microglial involvement in different forms of plasticity across developmental stages and brain regions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Aleksandra Paterek, Marta Okninska, Michal Maczewski, Urszula Mackiewicz
Summary: This study found that right ventricular failure caused by left ventricular failure cannot be solely explained by a decline in cardiomyocyte function. Other factors may play a role, highlighting the need for further research to better understand the biology of right ventricular failure and develop targeted therapies.
Article
Multidisciplinary Sciences
Niels Grote Beverborg, Daniela Spater, Ralph Knoll, Alejandro Hidalgo, Steve T. Yeh, Zaher Elbeck, Herman H. W. Sillje, Tim R. Eijgenraam, Humam Siga, Magdalena Zurek, Malin Palmer, Susanne Pehrsson, Tamsin Albery, Nils Bomer, Martijn F. Hoes, Cornelis J. Boogerd, Michael Frisk, Eva van Rooij, Sagar Damle, William E. Louch, Qing-Dong Wang, Regina Fritsche-Danielson, Kenneth R. Chien, Kenny M. Hansson, Adam E. Mullick, Rudolf A. de Boer, Peter van der Meer
Summary: The study shows that antisense inhibition of PLN is an effective therapeutic strategy in preclinical models of genetic cardiomyopathy and ischemia-driven heart failure, significantly improving cardiac function and survival rates.
NATURE COMMUNICATIONS
(2021)
Review
Rheumatology
Jakob Hoeppner, Cosimo Bruni, Oliver Distler, Simon C. Robson, Gerd R. Burmester, Elise Siegert, Jorg H. W. Distler
Summary: SSc is a chronic autoimmune rheumatic disease with histopathological hallmarks including vasculopathy, fibrosis, and autoimmune phenomena. Purinergic signalling pathway may play a role in the pathophysiology of SSc, exacerbating vasculopathy and immune dysregulation, while also promoting organ and tissue fibrosis. Targeting purinergic signalling could offer new therapeutic options for SSc.
Article
Medicine, General & Internal
Julia Hesse, Magdalena Siekierka-Harreis, Bodo Steckel, Christina Alter, Merle Schallehn, Nadine Honke, Marie-Laure Schnieringer, Madita Wippich, Rebekka Braband, Matthias Schneider, Harald Surowy, Dagmar Wieczorek, Jurgen Schrader, Georg Pongratz
Summary: This study identified a new pathomechanism for SLE, in which inactivation of CD73 on B cells results in reduced production of anti-inflammatory adenosine, leading to immune cell activation. The inactivation of CD73 was not due to genetic variation but may be related to posttranslational modification.
Review
Pharmacology & Pharmacy
Ankita Agrawal, Niklas R. Jorgensen
Summary: Maintaining a healthy skeleton relies on a complex regulation of bone metabolism, where physiological release of purines through purinoceptors plays a crucial role. Derivatives of adenosine released by bone cells are influenced by various factors such as mechanical loading, systemic hormones, and pathological conditions.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Cardiac & Cardiovascular Systems
Zhiyong Lei, Christine Wahlquist, Hamid el Azzouzi, Janine C. Deddens, Diederik Kuster, Alain van Mil, Agustin Rojas-Munoz, Manon M. Huibers, Mark Mercola, Roel de Weger, Jolanda van der Velden, Junjie Xiao, Pieter A. Doevendans, Joost P. G. Sluijter
Summary: miR-132/212 regulates cardiomyocyte contractility by targeting SERCA2a, with upregulation leading to impaired cardiac function. Pharmaceutical inhibition of miR-132/212 may be a promising therapeutic approach for heart failure patients.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2021)
Article
Neurosciences
Zheng Wei Wong, Tobias Engel
Summary: Epilepsy is a common neurological disease that affects people of all ages. Long-term video-electroencephalogram recordings are currently the gold standard for diagnosis, but they are expensive and limited in availability. The search for non-invasive diagnostic tests is ongoing, and purinergic signalling has shown potential as both a therapeutic strategy and a diagnostic tool for epilepsy management.
Article
Cell Biology
Roger Gregory Biringer
Summary: Migraine is a debilitating disorder characterized by throbbing and pulsating headaches, affecting more than 1 billion people worldwide. It is believed to be a neurovascular event involving vasoconstriction, vasodilation, and neuronal activation. Understanding the signaling pathways in migraine pathology is crucial for developing therapeutic strategies for migraine prevention and alleviating prodromal pain. The involvement of both vasoactivity and neural sensitization in migraine suggests that agonists promoting these phenomena may play a role in migraine pathology. This manuscript explores the relationship between purine metabolites and migraine pathology, using known signaling pathways.
MOLECULAR AND CELLULAR BIOCHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Lisa Ehlers, Aditi Kuppe, Alexandra Damerau, Siska Wilantri, Marieluise Kirchner, Philipp Mertins, Cindy Strehl, Frank Buttgereit, Timo Gaber
Summary: AMPD2 is expressed on the surface of human immune cells and may modify inflammatory states by altering the extracellular milieu. The expression of eAMPD2 on monocytes is enhanced after TLR stimulation. Patients with rheumatoid arthritis show significantly higher levels of eAMPD2 expression on PBMCs compared to healthy controls.
Review
Biochemistry & Molecular Biology
Mariachiara Zuccarini, Patricia Giuliani, Francesco Caciagli, Renata Ciccarelli, Patrizia Di Iorio
Summary: Bone remodeling is crucial for organic body growth and repair of trauma, with purines playing a key role in bone homeostasis by interacting with specific receptors on bone cells. While the effects of purines on bone through receptor interactions have been characterized, the role of extracellular enzymes in purine metabolism and their impact on bone health require further study.
Article
Biochemistry & Molecular Biology
Claudia Cano-Estrada, Lidia de Benito-Gomez, Paula Escudero-Ferruz, Neus Ontiveros, Daniel Iglesias-Serret, Jose M. Lopez
Summary: Most cancer cells increase the synthesis of purine nucleotides to support their rapid division. The use of cell culture media with physiological levels of folic acid revealed changes in purine metabolism in several human cell lines. Some cell lines accumulate the intermediate metabolite ZMP at physiological levels of folic acid, while others require artificially high levels of folic acid for ZMP accumulation. Further research is needed to understand the downstream targets of ZMP and their impact on cell function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Thomas Ihle Aarhus, Jan Eickhoff, Bert Klebl, Anke Unger, Joanna Boros, Axel Choidas, Mia -Lisa Zischinsky, Camilla Wolowczyk, Geir Bjorkoy, Eirik Sundby, Bard Helge Hoff
Summary: Through modelling, synthesis, and systematic structure-activity relationship study, a number of potent and highly selective purine-based inhibitors of CSF1R have been identified. Compound 9, the optimized 6,8-disubstituted antagonist, shows enzymatic IC50 of 0.2 nM and strong affinity towards the autoinhibited form of CSF1R.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Kiran S. Toti, Ryan G. Campbell, Hobin Lee, Veronica Salmaso, R. Rama Suresh, Zhan-Guo Gao, Kenneth A. Jacobson
Summary: Adenosine receptor (AR) ligands are being developed for the treatment of metabolic, cardiovascular, neurological, and inflammatory diseases and cancer. Fluorescent antagonist ligands were synthesized and screened for their affinities and selectivity towards different AR subtypes, showing potential as live cell or in vivo imaging tools and/or therapies.
PURINERGIC SIGNALLING
(2023)
Book Review
Chemistry, Medicinal
Kenneth A. Jacobson
Review
Biochemistry & Molecular Biology
Zhan-Guo Gao, John A. Auchampach, Kenneth A. Jacobson
Summary: Efforts to understand pharmacological differences between GPCR species homologues are generally not pursued in drug development. However, studying the pharmacological properties of the A(3) adenosine receptor (AR) is critical for understanding its biological functions. Pharmacological characterization of recombinant A(3)ARs from different species has been conducted.
PURINERGIC SIGNALLING
(2023)
Article
Neurosciences
Kenneth A. Jacobson, Balaram Pradhan, Zhiwei Wen, Asmita Pramanik
Summary: The discovery and clinical implementation of adenosine, P2Y and P2X receptor modulators have advanced significantly in the past 50 years. Although previous clinical trials of selective ligands have not been successful, there is now a renewed focus on new disease conditions and the development of more selective compounds, as well as the elucidation of new receptor and enzyme structures.
Article
Biochemistry & Molecular Biology
Cuiying Xiao, Oksana Gavrilova, Naili Liu, Sarah A. Lewicki, Marc L. Reitman, Kenneth A. Jacobson
Summary: Some drugs act on adenosine receptors (ARs) to produce effects, as demonstrated in mouse hypothermia experiments. Four drugs (dipyridamole, nimodipine, cilostazol, cyclosporin A) increased adenosine-induced hypothermia, while two drugs (cannabidiol, canrenoate) did not cause hypothermia. Four other drugs (nifedipine, ranolazine, ketamine, ethanol) caused hypothermia through non-adenosinergic mechanisms. Zinc chloride caused hypothermia and hypoactivity, which was reduced in mice lacking ARs. Interestingly, the antidepressant amitriptyline caused amplified hypothermia in mice lacking ARs. These findings suggest potential repurposing of adenosine-modulating drugs based on their effects on AR activation.
PURINERGIC SIGNALLING
(2023)
Article
Biochemistry & Molecular Biology
Federica Cherchi, Martina Venturini, Giada Magni, Mirko Scortichini, Kenneth A. Jacobson, Anna Maria Pugliese, Elisabetta Coppi
Summary: Recent studies have focused on the analgesic effects of adenosine and its receptors in chronic pain models. The A(3)AR receptor subtype has been found to reduce pro-nociceptive N-type Ca2+ channels, leading to inhibition of post inflammatory visceral hypersensitivity. This study investigates the effect of a previously reported irreversible A(3)AR agonist, ICBM, on Ca2+ currents in rat DRG neurons. The findings suggest that covalent A(3)AR agonists such as ICBM may offer a longer-lasting and more efficient strategy for chronic pain control compared to reversible A(3)AR agonists, but further pre-clinical studies are needed to address potential limitations and adverse effects.
PURINERGIC SIGNALLING
(2023)
Editorial Material
Pharmacology & Pharmacy
Francisco Ciruela, Kenneth A. Jacobson
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Multidisciplinary Sciences
Zhan-Guo Gao, Ian M. Levitan, Asuka Inoue, Qiang Wei, Kenneth A. Jacobson
Summary: Protein kinase C (PKC) isoforms can enhance A(2B) adenosine receptor (AR)-mediated cAMP accumulation through activation by phorbol 12-myristate 13-acetate (PMA), but do not enhance beta(2)-adrenergic receptor-mediated cAMP accumulation. PKC activation can also induce cAMP accumulation by activating A(2B)AR with high or low E-max. These findings are important for understanding the functions of A(2B)AR and PKC.
Article
Chemistry, Medicinal
Jung-Eun Park, Hobin Lee, Paola Oliva, Klara Kirsch, Bora Kim, Jong Il Ahn, Celeste N. Alverez, Snehal Gaikwad, Kristopher W. Krausz, Robert O'Connor, Ganesha Rai, Anton Simeonov, Beverly A. Mock, Frank J. Gonzalez, Kyung S. Lee, Kenneth A. Jacobson
Summary: Polo-like kinase 1 (Plk1) is an attractive target for anticancer drug discovery due to its widely upregulated activity in various human cancers. In addition to the kinase domain, the C-terminal noncatalytic polo-box domain (PBD) has emerged as an alternative target for developing inhibitors. Triazoloquinazolinone-derived inhibitors effectively block Plk1 with improved affinity and drug-like properties. Further derivatization is needed to improve the stability of these inhibitors for the development of therapeutics against Plk1-addicted cancers.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Qasim Shah, Zahid Hussain, Bilal Ahmad Khan, Kenneth A. Jacobson, Jamshed Iqbal
Summary: The study investigates the potency of P2X7 receptor antagonists and their relationship with cancer, revealing five compounds with strong selective inhibitory effects. These compounds exhibit varying cell viability and induction of apoptosis in transfected and non-transfected cell lines.
BIOORGANIC CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Katarina Mihajlovic, Marija Adzic Bukvic, Milorad Dragic, Mirko Scortichini, Kenneth A. Jacobson, Nadezda Nedeljkovic
Summary: In this in vitro study, three novel cytosine-derived alpha,beta-methylene diphosphonates (MRS4598, MRS4552, and MRS4602) were tested for their potency in inhibiting CD73 activity and attenuating reactive astrocyte phenotype. The results showed that all compounds exhibited concentration-dependent inhibition of CD73 activity with high inhibitory potency and binding capacity. Among them, MRS4598 was the most effective in inhibiting CD73 activity and inducing reactive astrocyte phenotype inhibition, making it a promising tool for the treatment of neurodegeneration and neuroinflammation.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Zhiwei Wen, Asmita Pramanik, Sarah A. Lewicki, Young-Hwan Jung, Zhan-Guo Gao, John C. R. Randle, Chunxia Cronin, Zhoumou Chen, Luigino A. Giancotti, Gregory S. Whitehead, Bruce T. Liang, Sylvie Breton, Daniela Salvemini, Donald N. Cook, Kenneth A. Jacobson
Summary: P2Y(14) receptor is activated by extracellular UDP-glucose, promoting inflammation in various tissues. Selective P2Y(14)R antagonists could be useful for inflammatory and metabolic diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Hai-Jun Zhang, Michal Ociepa, Molhm Nassir, Bin Zheng, Sarah A. Lewicki, Veronica Salmaso, Helay Baburi, Jessica Nagel, Salahuddin Mirza, Haneen Al-Hroub, Beatriz Bueschbell, Olga Perzanowska, Ziqin Lin, Michael A. Schmidt, Martin D. Eastgate, Kenneth A. Jacobson, Christa E. Mueller, Joanna Kowalska, Jacek Jemielity, Phil S. Baran
Summary: Nucleoside diphosphates and triphosphates have a profound impact on biochemistry, but their usage as tools or medicinal leads for nucleotide-dependent enzymes and receptors is hindered by their rapid metabolism in the body. This study demonstrates the development of a modular, reagent-based platform that allows the stereocontrolled and scalable synthesis of pure stereoisomers of nucleoside thioisosteres, which can have significant effects on ligand-receptor interactions.
Article
Chemistry, Medicinal
Eline Pottie, R. Rama Suresh, Kenneth A. Jacobson, Christophe P. Stove
Summary: This study aimed to explore inverse agonism at A(3)AR using two engineered cell lines and NanoBiT technology. The previously established inverse agonist PSB-10 showed inverse agonism in one assay but not in another. Further experiments confirmed the specificity and reversibility of this observation. Evaluation of presumed neutral antagonists revealed their concentration-dependent inverse agonism in the A(3)AR-βarr2 recruitment assay.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Chemistry, Medicinal
Dilip K. Tosh, Courtney L. Fisher, Veronica Salmaso, Tina C. Wan, Ryan G. Campbell, Eric Chen, Zhan-Guo Gao, John A. Auchampach, Kenneth A. Jacobson
Summary: (N)-Methanocarba adenosine derivatives were modified to form macrocyclic A(3) adenosine receptor agonists. These macrocycles retained affinity and had a spatially proximal orientation on the receptor. C2-Arylethynyl-linked macrocycle 19 showed higher selectivity for A(3) adenosine receptor compared to 2-ether-linked macrocycle 12.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)