Article
Chemistry, Multidisciplinary
R. Rama Suresh, Russell B. Poe, Baorui Lin, Kexin Lv, Ryan G. Campbell, Zhan-Guo Gao, Theodore E. Liston, Kiran S. Toti, Kenneth A. Jacobson
Summary: A linear route is used to prepare (N)-methanocarba-nucleoside derivatives with a pre-established receptor-preferred conformation, which bind to receptors after functional group modifications. The method provides moderate to good yield by introducing a rigid ribose substitute and conserving key intermediate 3 in nine sequential steps. The general applicability of this convergent synthesis for various substituents demonstrates its efficacy as an optimized preclinical synthetic route.
Article
Chemistry, Medicinal
Dilip K. Tosh, Maggie M. Calkins, Marko S. Ivancich, Hailey A. Bock, Ryan G. Campbell, Sarah A. Lewicki, Eric Chen, Zhan-Guo Gao, John D. Mccorvy, Kenneth A. Jacobson
Summary: Derivatives of (N)-Methanocarba adenosine were modified to target 5-HT2B serotonin receptors as antagonists, showing affinity enhancement with the bicyclic ring system. Compound 43 (MRS7925) exhibited potential for anti-fibrotic therapy due to its affinity and moderate 5-HT2BR binding selectivity. The compounds also demonstrated dual action as 5-HT2B antagonists and A(1)AR agonists.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Kenneth A. Jacobson, Veronica Salmaso, R. Rama Suresh, Dilip K. Tosh
Summary: Nucleoside derivatives, especially those with bicyclic ring systems, have shown potential as pharmaceuticals by targeting various receptors and signaling pathways. By modifying the structure of nucleosides, researchers have been able to enhance their potency and selectivity, leading to the discovery of novel interactions with different protein targets and revealing previously unknown antiviral activities. Through these advancements, a robust purinergic receptor scaffold has been repurposed to satisfy the pharmacophoric requirements of various GPCRs, enzymes and transporters.
RSC MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Cristina Val, Carlos Rodriguez-Garcia, Ruben Prieto-Diaz, Abel Crespo, Jhonny Azuaje, Carlos Carbajales, Maria Majellaro, Alejandro Diaz-Holguin, Jose M. Brea, Maria Isabel Loza, Claudia Gioe-Gallo, Marialessandra Contino, Angela Stefanachi, Xerardo Garcia-Mera, Juan C. Estevez, Hugo Gutierrez-de-Teran, Eddy Sotelo
Summary: This study documents a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent A(1)AR ligands, confirming their selectivity and structure-activity relationships. The study highlights the influence of aromatic residues at positions R-4 and R-6 of the pyrimidine core, as well as the role of a methyl group at the exocyclic amino group on A(1)AR selectivity profile.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Jeroen Spanoghe, Lars E. Larsen, Erine Craey, Simona Manzella, Annelies Van Dycke, Paul Boon, Robrecht Raedt
Summary: Activation of adenosine A(1) receptor can inhibit seizures through various signaling pathways leading to neuronal inhibition. However, chronic activation of the A(1) receptor may have detrimental effects that should be avoided in the development of epilepsy therapies based on this receptor.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Katarzyna Bednarska-Szczepaniak, Adam Mieczkowski, Aleksandra Kierozalska, Dijana Pavlovic Saftic, Konrad Glabala, Tomasz Przygodzki, Lidia Stanczyk, Kamil Karolczak, Cezary Watala, Harsha Rao, Zhan-Guo Gao, Kenneth A. Jacobson, Zbigniew J. Lesnikowski
Summary: A series of adenosine and 2'-deoxyadenosine pairs modified with a boron cluster or phenyl group showed a general tendency to preferentially bind to the A(3) adenosine receptor. Boron cluster-modified ligands exhibited higher A(3) receptor selectivity compared to phenyl analogs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Maria Ya Berzina, Barbara Z. Eletskaya, Alexei L. Kayushin, Elena Dorofeeva, Olga Lutonina, Ilya Fateev, Alexander S. Paramonov, Maria A. Kostromina, Evgeniy A. Zayats, Yulia A. Abramchik, Dmitriy Maltsev, Ludmila Naumenko, Alena S. Taran, Dmitry S. Yakovlev, Alexander A. Spasov, Anatoly Miroshnikov, Roman S. Esipov, Irina D. Konstantinova
Summary: A series of purine ribonucleosides with chiral amino acid amides were synthesized and their affinity for A(1) adenosine receptors (A(1)ARs) was investigated. It was found that some of the synthesized nucleosides exhibited partial agonist activity towards A(1)ARs and showed different profiles of psychoactive action and ocular hypotensive effect.
BIOORGANIC CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Zachary Carlson, Kelly Drew
Summary: Hibernation is an adaptation that allows animals to survive without food or water. Understanding the mechanisms of metabolic suppression during hibernation could lead to new treatments in critical care. The activation of Adenosine A(1) receptor (A(1)AR) plays a role in hibernation, but its role in seasonal sensitization is unknown. In this study, the A(1)AR in different brain regions of Arctic ground squirrels during summer and torpor seasons was characterized, and the pharmacological characteristics of A(1)AR agonist and antagonist were defined.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Medicine, Research & Experimental
Linlin Bi, Yang Liu, Qian Yang, Xuanxuan Zhou, Hua Li, Jie Li, Yunyang Lu, Haielng Tang
Summary: The study investigated the effects of Paris saponin H (PSH) on U251 glioblastoma cells and found that PSH inhibited cell viability, migration, invasion, induced apoptosis, and cell cycle arrest by inhibiting ARA1 and ARA3 expression, repressing Akt and 44/42 MAPK phosphorylation.
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
(2021)
Article
Endocrinology & Metabolism
Mitchell E. Granade, Stefan R. Hargett, Daniel S. Lank, Michael C. Lemke, Melissa A. Luse, Brant E. Isakson, Irina M. Bochkis, Joel Linden, Thurl E. Harris
Summary: Adipose tissue response to adenosine changes dynamically according to nutrient conditions through the insulin-Akt-FOXO1 axis. Deletion of adipocyte A1R leads to impairments in lipolysis suppression by insulin under fasting conditions and compromised glucose tolerance. Refeeding results in downregulation of A1R transcription and desensitization of adipocytes to A1R agonism, facilitating reentrance into the catabolic state upon fasting.
MOLECULAR METABOLISM
(2022)
Article
Endocrinology & Metabolism
Mitchell E. Granade, Stefan R. Hargett, Daniel S. Lank, Michael C. Lemke, Melissa A. Luse, Brant E. Isakson, Irina M. Bochkis, Joel Linden, Thurl E. Harris
Summary: This study reveals that adenosine regulates adipocyte metabolism through A1R, with adipose tissue exhibiting dynamic responses to adenosine under fasting and feeding conditions. High A1R expression under fasting limits excessive lipolysis, while downregulation of A1R under feeding leads to desensitization of adipocytes to A1R.
MOLECULAR METABOLISM
(2022)
Article
Immunology
Henrique Ballassini Abdalla, Marcelo Henrique Napimoga, Alexandre Gomes de Macedo Maganin, Alexandre Hashimoto Lopes, Thiago Mattar Cunha, Harvinder Singh Gill, Juliana Trindade Clemente-Napimoga
Summary: The study found that tramadol's peripheral analgesic and anti-inflammatory effects in the temporomandibular joint (TMJ) are mediated by adenosine A1 receptors and involve increased protein expression of alpha 2a-adrenoceptor.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2021)
Article
Neurosciences
Renee Chasse, Alexey Malyshev, Roslyn Holly Fitch, Maxim Volgushev
Summary: Theoretical and modeling studies suggest that heterosynaptic plasticity enhances discriminative learning and repetitive learning in Hebbian-type systems. Experimental manipulation of adenosine A1 receptors (A1Rs) to impair heterosynaptic plasticity resulted in impaired synaptic plasticity and deficits in visual discrimination learning in A1R KO mice. These results provide experimental evidence for the role of heterosynaptic plasticity in organism-level learning and suggest it as a potential target for interventions to enhance new learning.
JOURNAL OF NEUROSCIENCE
(2021)
Article
Medicine, Research & Experimental
Johanna C. Arroyave-Ospina, Manon Buist-Homan, Martina Schmidt, Han Moshage
Summary: This study found that caffeine can protect liver cells from the toxic effects of fatty acids by modulating adenosine receptor signaling. By activating protein kinase A and inhibiting the A1AR receptor, caffeine can reduce lipid accumulation and harmful substances produced by mitochondria, thereby alleviating metabolic dysfunction-associated liver disease.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Biochemistry & Molecular Biology
Erine Craey, Fabian Hulpia, Jeroen Spanoghe, Simona Manzella, Lars E. Larsen, Mathieu Sprengers, Dimitri De Bundel, Ilse Smolders, Evelien Carrette, Jean Delbeke, Kristl Vonck, Paul Boon, Serge Van Calenbergh, Wytse J. Wadman, Robrecht Raedt
Summary: This study reports the design, synthesis, and validation of a novel compound that can precisely release adenosine A1 receptor agonist using light. By monitoring the strength of neurotransmission and controlling the release of light, the study achieved regulation of neurotransmission. This research method is of great significance for the treatment of diseases associated with neuronal hyperexcitability.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
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
Chemistry, Medicinal
Dilip K. Tosh, Maggie M. Calkins, Marko S. Ivancich, Hailey A. Bock, Ryan G. Campbell, Sarah A. Lewicki, Eric Chen, Zhan-Guo Gao, John D. Mccorvy, Kenneth A. Jacobson
Summary: Derivatives of (N)-Methanocarba adenosine were modified to target 5-HT2B serotonin receptors as antagonists, showing affinity enhancement with the bicyclic ring system. Compound 43 (MRS7925) exhibited potential for anti-fibrotic therapy due to its affinity and moderate 5-HT2BR binding selectivity. The compounds also demonstrated dual action as 5-HT2B antagonists and A(1)AR agonists.
EUROPEAN JOURNAL OF MEDICINAL 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)