Review
Endocrinology & Metabolism
Anh T. N. Nguyen, Quan L. Tran, Jo-Anne Baltos, Samantha M. McNeill, Diep T. N. Nguyen, Lauren T. May
Summary: G protein-coupled receptors (GPCRs) are targeted by approximately one-third of FDA-approved small molecule drugs. Among the four adenosine GPCR subtypes, the adenosine A(1) receptor (A(1)R) plays important physiological roles in humans. A(1)R has been identified as a potential therapeutic target for various conditions, but the development of small molecule drugs targeting A(1)R has been limited by unwanted effects. An alternative approach using A(1)R allosteric modulators that target a different binding site shows promise in overcoming these limitations. This review provides insights into the therapeutic potential of A(1)R and recent advances in understanding its allosteric modulation.
FRONTIERS IN ENDOCRINOLOGY
(2023)
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)
Article
Chemistry, Applied
Chandresh Kumari, Avijit Goswami
Summary: An atom-economical approach for the synthesis of 3-aminofurans/thiophenes via conjugate addition and modified Thorpe-Ziegler cyclization has been reported. This operationally simple method offers a rapid access to a diverse library of compounds.
ADVANCED SYNTHESIS & CATALYSIS
(2022)
Article
Chemistry, Medicinal
Jon Kyle Awalt, Anh T. N. Nguyen, Tim J. Fyfe, Bui San Thai, Paul J. White, Arthur Christopoulos, Manuela Joerg, Lauren T. May, Peter J. Scammells
Summary: The adenosine A(1) receptor is a therapeutic target for cardioprotection during myocardial ischemia and reperfusion injury. However, clinical translation of A(1)R agonists is hindered by dose-limiting adverse effects. The bitopic agonist VCP746, consisting of an adenosine pharmacophore linked to an allosteric moiety, has shown promising results in stimulating cardioprotective A(1)R signaling effects without unwanted bradycardia. This study investigates the structure-activity relationships of VCP746 and identifies the most potent A2BR agonist to date.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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
Pharmacology & Pharmacy
Kequan Fu, Wenbing Chen, Mingzhu Meng, Huimin Zhao, Haoxing Yuan, Yinan Wang, Ying Ren, Yi Yun, Dong Guo
Summary: The adenosine A1 receptor is an important target for metabolic disorders and plays a significant role in regulating free fatty acid levels. This study examined the effect of an allosteric modulator on the action of an A1 receptor agonist in regulating lipolysis. The results showed that the allosteric modulator enhanced the antilipolytic action of the agonist by slowing down its dissociation from the receptor and downregulating the cAMP/HSL pathway. This study highlights the potential application of A1 receptor allosteric modulators in the treatment of metabolic diseases.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
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
Pharmacology & Pharmacy
Luisa Saecker, Hanns Haeberlein, Sebastian Franken
Summary: In this study, a live cell assay for A(1)AR-mediated beta-arrestin 2 recruitment was characterized. The assay showed that Capadenoson exhibited partial agonism in beta-arrestin 2 recruitment, but full agonism in the inhibitory effect on cAMP production. Furthermore, it was demonstrated for the first time that a valerian extract can stimulate A(1)AR-mediated beta-arrestin 2 recruitment.
FRONTIERS IN PHARMACOLOGY
(2023)
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
Biology
Shuya Kate Huang, Omar Almurad, Reizel J. Pejana, Zachary A. Morrison, Aditya Pandey, Louis-Philippe Picard, Mark Nitz, Adnan Sljoka, R. Scott Prosser
Summary: Cholesterol indirectly modulates the conformational equilibria and signaling of the adenosine A(2A) receptor by influencing membrane properties.
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
Biochemistry & Molecular Biology
Elisabetta Barresi, Chiara Giacomelli, Laura Marchetti, Emma Baglini, Silvia Salerno, Giovanni Greco, Federico Settimo, Claudia Martini, Maria Letizia Trincavelli, Sabrina Taliani
Summary: The study investigated compounds with chemical similarity to known PAMs of A(2B) AR, identifying lead compounds with potential as anti-osteoporosis agents. Further characterization of benzofurane derivative 9 confirmed its role as a PAM of A(2B) AR.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
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
Pharmacology & Pharmacy
Kristy L. Meads, Thaddeus P. Thomas, Jeffrey L. Langston, Todd M. Myers, Tsung-Ming Shih
Summary: The study found that A1AR agonists can provide neuroprotection and prevent cognitive and behavioral deficits caused by soman poisoning. The use of an active avoidance shuttle box task showed that animals treated with A1AR agonists exhibited more avoidance responses and a faster reaction to aversive stimuli compared to the soman/saline control group.
TOXICOLOGY AND APPLIED PHARMACOLOGY
(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
Chemistry, Medicinal
Shailesh N. Mistry, Manuela Joerg, Herman Lim, Natalie B. Vinh, Patrick M. Sexton, Ben Capuano, Arthur Christopoulos, J. Robert Lane, Peter J. Scammells
JOURNAL OF MEDICINAL CHEMISTRY
(2016)
Article
Biochemistry & Molecular Biology
Shailesh N. Mistry, Herman Lim, Manuela Joerg, Ben Capuano, Arthur Christopoulos, J. Robert Lane, Peter J. Scammells
ACS CHEMICAL NEUROSCIENCE
(2016)
Article
Chemistry, Multidisciplinary
Jon Kyle Awalt, Raymond Lam, Barrie Kellam, Bim Graham, Peter J. Scammells, Robert D. Singer
Article
Medicine, Research & Experimental
Yasemin Sahbaz, Tri-Hung Nguyen, Leigh Ford, Claire L. McEvoy, Hywel D. Williams, Peter J. Scammells, Christopher J. H. Porter
MOLECULAR PHARMACEUTICS
(2017)
Article
Chemistry, Multidisciplinary
Karina Pombo-Garcia, Carmen L. Ruehl, Raymond Lam, Jose A. Barreto, Ching-Seng Ang, Peter J. Scammells, Peter Comba, Leone Spiccia, Bim Graham, Tanmaya Joshi, Holger Stephan
Article
Pharmacology & Pharmacy
Christopher J. Draper-Joyce, Mayako Michino, Ravi Kumar Verma, Carmen Klein Herenbrink, Jeremy Shonberg, Anitha Kopinathan, Peter J. Scammells, Ben Capuano, David M. Thal, Jonathan A. Javitch, Arthur Christopoulos, Lei Shi, J. Robert Lane
BIOCHEMICAL PHARMACOLOGY
(2018)
Article
Chemistry, Medicinal
Raymond Lam, Arisbel B. Gondin, Meritxell Canals, Barrie Kellam, Stephen J. Briddon, Bim Graham, Peter J. Scammells
JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Chemistry, Medicinal
Luigi Aurelio, Jo-Anne Baltos, Leigh Ford, Anh T. N. Nguyen, Manuela Jorg, Shane M. Devine, Celine Valant, Paul J. White, Arthur Christopoulos, Lauren T. May, Peter J. Scanunells
JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Chemistry, Medicinal
Juliana C. C. Dallagnol, Elham Khajehali, Emma T. van der Westhuizen, Manuela Jorg, Celine Valant, Alan G. Goncalves, Ben Capuano, Arthur Christopoulos, Peter J. Scammells
JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Chemistry, Medicinal
Hywel D. Williams, Leigh Ford, Shea Lim, Sifei Han, John Baumann, Hannah Sullivan, David Vodak, Annabel Igonin, Hassan Benameur, Colin W. Pouton, Peter J. Scammells, Christopher J. H. Porter
JOURNAL OF PHARMACEUTICAL SCIENCES
(2018)
Article
Pharmacology & Pharmacy
Emma T. van der Westhuizen, Arthur Spathis, Elham Khajehali, Manuela Jorg, Shailesh N. Mistry, Ben Capuano, Andrew B. Tobin, Patrick M. Sexton, Peter J. Scammells, Celine Valant, Arthur Christopoulos
MOLECULAR PHARMACOLOGY
(2018)
Article
Multidisciplinary Sciences
Christopher J. Draper-Joyce, Ravi Kumar Verma, Mayako Michino, Jeremy Shonberg, Anitha Kopinathan, Carmen Klein Herenbrink, Peter J. Scammells, Ben Capuano, Ara M. Abramyan, David M. Thal, Jonathan A. Javitch, Arthur Christopoulos, Lei Shi, J. Robert Lane
SCIENTIFIC REPORTS
(2018)
Article
Chemistry, Medicinal
Shane M. Devine, Cassandra Yong, Dzifa Amenuvegbe, Luigi Aurelio, Divya Muthiah, Colin Pouton, Richard Callaghan, Ben Capuano, Peter J. Scammells
JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Medicine, Research & Experimental
Hywel D. Williams, Leigh Ford, Sifei Han, Kristian J. Tangso, Shea Lim, David M. Shackleford, David T. Vodak, Hassan Benameur, Colin W. Pouton, Peter J. Scammells, Christopher J. H. Porter
MOLECULAR PHARMACEUTICS
(2018)
Article
Biochemistry & Molecular Biology
Alisa Glukhova, David M. Thal, Anh T. Nguyen, Elizabeth A. Vecchio, Manuela Jorg, Peter J. Scammells, Lauren T. May, Patrick M. Sexton, Arthur Christopoulos