Article
Chemistry, Medicinal
Hongseok Choi, Kenneth A. Jacobson, Jinha Yu, Lak Shin Jeong
Summary: This study describes a new series of compounds as highly potent and selective human A(3) adenosine receptor (hA(3)AR) antagonists, with the derivative 2-H-N-6-3-iodobenzylamine exhibiting the highest binding affinity at hA(3)AR. Addition of a second N-methyl group to convert A(3)AR agonists into antagonists was successful, and the hydrogen of 5'-uronamide was identified to play an essential role in hA(3)AR activation as a hydrogen bonding donor.
Article
Pharmacology & Pharmacy
Marc Lopez-Cano, Ingrid Filgaira, Ernest G. Nolen, Gisela Cabre, Jordi Hernando, Dilip K. Tosh, Kenneth A. Jacobson, Concepcio Soler, Francisco Ciruela
Summary: Psoriasis is a chronic inflammatory skin disease affecting approximately 2% of the population, with defective keratinocyte proliferation and differentiation, along with aberrant immune responses being major factors in its pathogenesis. Current treatments for moderate to severe psoriasis may lead to systemic immunosuppression and serious side effects, such as infections and cancer. In recent years, the A(3) receptor for adenosine has emerged as a promising therapeutic target for psoriasis, showing robust anti-inflammatory effects in animal models of autoimmune inflammatory diseases.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Andrology
Inbal Itzhak, Shira Cohen, Sari Fishman, Pnina Fishman
Summary: CF602 treatment significantly improved erectile function in a diabetic ED rat model, and further evaluation of its efficacy as a treatment for ED is supported.
Article
Chemistry, Organic
Lidong Shan, Hongchen Li, Weiping Zheng, Xingyong Wang, Xinyan Wang, Yuefei Hu
Summary: Direct evidence explaining why 2-propynamides have never been used as substrates in Tf2O-promoted electrophilic activations was obtained. Furthermore, a new method for the synthesis of structurally special 2,4-disubstituted quinolines was developed, allowing easy diversification of the substituent at position 2 of quinolines.
Article
Chemistry, Medicinal
Lucas B. Fallot, R. Rama Suresh, Courtney L. Fisher, Veronica Salmaso, Robert D. O'Connor, Noy Kaufman, Zhan-Guo Gao, John A. Auchampach, Kenneth A. Jacobson
Summary: In this study, we synthesized new analogues to distinguish between 2-cyclopropyl antagonists and derivatives with large alkyl/cycloalkyl/bicycloalkyl groups as positive allosteric modulators (PAMs) for A3 adenosine receptor (A3AR). We predicted the binding of PAMs at a hydrophobic site on the A3AR cytosolic interface. Some derivatives, such as 2-cyclohept-4-enyl-N-3,4-dichlorophenyl and 2-heptan-4-yl-N-4-iodophenyl, showed good oral bioavailability in rats and significantly enhanced the binding effect of Cl-IB-MECA stimulation.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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
Chemistry, Medicinal
Andrea Spinaci, Michela Buccioni, Diego Dal Ben, Federica Maggi, Gabriella Marucci, Beatrice Francucci, Giorgio Santoni, Catia Lambertucci, Rosaria Volpini
Summary: The study identified a potential anti-tumor agent that exhibited significant cytostatic activity on prostate cancer cell lines, suggesting it could become a new approach in diagnosis and treatment.
Article
Chemistry, Medicinal
Dilip K. Tosh, Veronica Salmaso, Ryan G. Campbell, Harsha Rao, Amelia Bitant, Eline Pottie, Christophe P. Stove, Naili Liu, Oksana Gavrilova, Zhan-Guo Gao, John A. Auchampach, Kenneth A. Jacobson
Summary: By incorporating dopamine-related substituents, we have developed highly potent mouse A(3)AR agonists. Computational modeling and functional assays indicate that the enhanced affinity of these new compounds may be attributed to their interaction with polar residues on the mA(3)AR. Additionally, we observed peripheral A(3)AR agonism in vivo for these compounds.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Dario Miranda-Pastoriza, Rodrigo Bernardez, Jhonny Azuaje, Ruben Prieto-Diaz, Maria Majellaro, Ashish Tamhankar, Lucien Koenekoop, Alejandro Gonzalez, Claudia Gioe-Gallo, Ana Mallo-Abreu, Jose Brea, M. Isabel Loza, Aitor Garcia-Rey, Xerardo Garcia-Mera, Hugo Gutierrez-de-Teran, Eddy Sotelo
Summary: This study designed a library of highly selective pyrimidine-based compounds to explore non-orthosteric interactions within the A3AR receptor. Through structure-based design, the solubility of the synthesized compounds was improved, and the impact of functionalized residues on structural tolerability was evaluated. The study provides clues for further development of novel A3AR ligands.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
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
Clinical Neurology
Theodore E. Liston, Aldric Hama, Johannes Boltze, Russell B. Poe, Takahiro Natsume, Ikuo Hayashi, Hiroyuki Takamatsu, William S. Korinek, James D. Lechleiter
Summary: This study demonstrates the therapeutic effect of AST-004 agonist in the treatment of acute ischemic stroke in a nonhuman primate model. AST-004 reduces lesion volume and increases penumbra volume. The changes are correlated with unbound AST-004 concentrations in the plasma and cerebrospinal fluid as well as estimated brain A1R and A3R occupancy.
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
R. Rama Suresh, Zhan-Guo Gao, Veronica Salmaso, Eric Chen, Ryan G. Campbell, Russell B. Poe, Theodore E. Liston, Kenneth A. Jacobson
Summary: The structure-activity relationship of an A3AR antagonist has been explored and a high-affinity radioligand has been developed, which shows promise as a useful tool for receptor characterization and drug discovery.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Pharmacology & Pharmacy
Pengfei Cheng, Junxiang Zhang, Zhensheng Chu, Wenting Liu, Hao Lin, Yu Wu, Jiaying Zhu
Summary: The study found that the A3 adenosine receptor agonist can improve memory deficits caused by chronic cerebral ischemia, and regulate brain inflammation by modulating the ERK signaling pathway and protecting protein expression.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Carmen Tarifa, Veronica Jimenez-Sabado, Rafael Franco, Jose Montiel, Jose Guerra, Francisco Ciruela, Leif Hove-Madsen
Summary: Increased activation of adenosine A(2A) receptors (A(2A)Rs) leads to higher incidence of spontaneous calcium release in atrial fibrillation (AF). Adenosine A(3) receptors (A(3)Rs) can counteract excessive A(2A)R activation, but their role in the atrium is not well understood. This study found that A(3)Rs inhibit spontaneous calcium release in human atrial myocytes and can attenuate pathological elevations in calcium release events, suggesting their potential therapeutic importance.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Tamara A. M. Mocking, Hubert J. Sijben, Yime W. Vermeulen, Adriaan P. IJzerman, Laura H. Heitman
Summary: In this study, a label-free impedance-based transport assay was developed to detect OCT-mediated transport activity and inhibition. The method was effective in both OCT1-3 overexpressing cells and HeLa cells endogenously expressing OCT3, providing a valuable tool for studying drug-drug interactions and identifying potential inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Anna Vlachodimou, Henk de Vries, Milena Pasoli, Miranda Goudswaard, Soon-Ai Kim, Yong-Chul Kim, Mirko Scortichini, Melissa Marshall, Joel Linden, Laura H. Heitman, Kenneth A. Jacobson, Adriaan P. IJzerman
Summary: A(2B) adenosine receptor (A(2B)AR) antagonists have therapeutic potential in inflammation-related diseases, but there is a need for novel antagonists. This study investigates the synthesis and biological evaluation of xanthine derivatives as A(2B)AR antagonists. The study finds a clear relationship between a ligand's A(2B)AR residence time and its functional effect, highlighting the importance of binding kinetics in early drug discovery.
BIOCHEMICAL PHARMACOLOGY
(2022)
Review
Cardiac & Cardiovascular Systems
Marios K. Georgakis, Juergen Bernhagen, Laura H. Heitman, Christian Weber, Martin Dichgans
Summary: Decades of research have established atherosclerosis as an inflammatory disease. Clinical trials have shown the efficacy of anti-inflammatory strategies in reducing cardiovascular events, but there is a need for new anti-inflammatory agents that target atherosclerosis-specific immune mechanisms. The CCL2-CCR2 axis has therapeutic potential in human atherosclerosis. However, there are challenges and opportunities related to pharmacological targeting of this pathway that need further investigation and discussion.
EUROPEAN HEART JOURNAL
(2022)
Article
Pharmacology & Pharmacy
L. S. den Hollander, O. J. M. Bequignon, X. Wang, K. van Wezel, J. Broekhuis, M. Gorostiola Gonzalez, K. E. de Visser, A. P. IJzerman, G. J. P. van Westen, L. H. Heitman
Summary: CCR2, a G protein-coupled receptor, is involved in various cancer-related processes. Mutations in CCR2 were investigated for their impact on receptor functionality and antagonist binding. Most mutants showed a decrease in G protein activation in response to the main ligand, while orthosteric antagonist binding was affected by specific mutations and allosteric antagonist binding was completely abolished in certain mutants. Considering CCR2 as a potential drug target in cancer, the negative effects of these mutations on receptor functionality and drug development should be considered.
BIOCHEMICAL PHARMACOLOGY
(2023)
Correction
Pharmacology & Pharmacy
L. S. den Hollander, O. J. M. Bequignon, X. Wang, K. van Wezel, J. Broekhuis, M. Gorostiola Gonzalez, K. E. de Visser, A. P. IJzerman, G. J. P. van Westen, L. H. Heitman
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Brandon J. Bongers, Huub J. Sijben, Peter B. R. Hartog, Andrey Tarnovskiy, Adriaan P. IJzerman, Laura H. Heitman, Gerard J. P. van Westen
Summary: In this study, a computational screening pipeline was developed to find new inhibitors for the NET protein. A data-driven approach was used to diversify the chemical space and select optimal proteins to model for NETs. A proteochemometric model was created and applied to an extensive compound database, resulting in the identification of five potential hit compounds with promising inhibitory potencies toward NET.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Multidisciplinary Sciences
Xiaoting Li, Hao Chang, Jara Bouma, Laura V. de Paus, Partha Mukhopadhyay, Janos Paloczi, Mohammed Mustafa, Cas van der Horst, Sanjay Sunil Kumar, Lijie Wu, Yanan Yu, Richard J. B. H. N. van den Berg, Antonius P. A. Janssen, Aron Lichtman, Zhi-Jie Liu, Pal Pacher, Mario van der Stelt, Laura H. Heitman, Tian Hua
Summary: In this study, the authors report the discovery of a CB2R agonist, LEI-102, and investigate its selective activation of CB2R in conjunction with three other CBR ligands (APD371, HU308, and CP55,940). They identify key residues for CB2R activation and reveal the important role of lipophilicity in CB2R engagement. The favorable physico-chemical properties of LEI-102 enable its oral efficacy in a chemotherapy-induced nephropathy model.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Alena I. Siutkina, Svetlana Kalinina, Rongfang Liu, Laura H. Heitman, Anna Junker, Constantin G. Daniliuc, Dmitrii V. Kalinin
Summary: We report the microwave-assisted synthesis of previously unreported 6-methoxy-5,6-dihydro-5-azapurines, which have a promising purinelike scaffold for drug discovery. The method is simple and fast, using easily accessible reagents such as trimethyl orthoformate, acetic acid, and aminotriazole-derived N,N'-disubstituted formamidines. Preliminary biological evaluation showed that the synthesized 6-methoxy-5,6-dihydro-5-azapurines dose-dependently reduce the viability of HepG2 and A549 cancer cells with little to no influence on five tested purinergic receptors.
Article
Chemistry, Medicinal
Alessio Ciulli, Suzanne O'Connor, Chun-Wa Chung, Ingo V. Hartung, Andrea Testa, Danette L. Daniels, Laura H. Heitman
Summary: This report provides an overview of the 17th EFMC Short Course on Medicinal Chemistry, highlighting the inclusion of the exciting topic of Targeted Protein Degradation. It summarizes the successful event and key lectures, as well as the diverse representation of attendees from Europe, the US, and South Africa.
Article
Chemistry, Medicinal
Bert L. H. Beerkens, Inge M. Snijders, Joep Snoeck, Rongfang Liu, Anton T. J. Tool, Sylvia E. Le Devedec, Willem Jespers, Taco W. Kuijpers, Gerard J. P. van Westen, Laura H. Heitman, Adriaan P. IJzerman, Daan van der Es
Summary: This article describes the development of a new probe for detecting human A(3)AR, which has been validated through radioligand displacement, SDS-PAGE, confocal microscopy, and flow cytometry experiments. The probe is expected to be of great significance for future studies on the expression and function of A(3)AR in pathologies.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Anna Vlachodimou, Jara Bouma, Michel De Cleyn, Didier Berthelot, Stefan Pype, Jean-Paul Bosmans, Herman van Vlijmen, Berthold Wroblowski, Laura H. Heitman, Adriaan P. IJzerman
Summary: Evaluation of kinetic parameters of drug-target binding, k(on), k(off), and residence time (RT), in addition to the traditional in vitro parameter of affinity is receiving increasing attention in the early stages of drug discovery. Target binding kinetics emerges as a meaningful concept for the evaluation of a ligand's duration of action and more generally drug efficacy and safety. We report the biological evaluation of a novel series of spirobenzo-oxazinepiperidinone derivatives as inhibitors of the human equilibrative nucleoside transporter 1 (hENT1, SLC29A1).
PURINERGIC SIGNALLING
(2023)
Article
Chemistry, Medicinal
Brandon J. Bongers, Huub J. Sijben, Peter B. R. Hartog, Andrey Tarnovskiy, Adriaan P. IJzerman, Laura H. Heitman, Gerard J. P. van Westen
Summary: This study developed a computational screening pipeline to identify new inhibitors for the high-affinity norepinephrine transporter (NET). By using the chemical space of related proteins, a data-driven approach was used to diversify the known chemical space for NET modeling. The final model, created through a two-step approach, predicted 46 chemically diverse candidates, of which five compounds showed promising inhibitory potency towards NET in experimental assays.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Bert L. H. Beerkens, Cagla Koc, Rongfang Liu, Bogdan I. Florea, Sylvia E. Le Devedec, Laura H. Heitman, Adriaan P. IJzerman, Daan Van Der Es
Summary: G protein-coupled receptors (GPCRs) have long been recognized as attractive drug targets, but many aspects of GPCR signaling remain poorly understood due to the difficulties encountered in studying them. In this study, we have developed an affinity-based probe for a prototype GPCR, the adenosine A(1) receptor (A(1)AR), and conducted various biochemical assays to evaluate its efficacy.
ACS CHEMICAL BIOLOGY
(2022)
