Article
Endocrinology & Metabolism
Kaleeckal G. Harikumar, Thomas Coudrat, Aditya J. Desai, Maoqing Dong, Daniela G. Dengler, Sebastian G. B. Furness, Arthur Christopoulos, Denise Wootten, Eduard A. Sergienko, Patrick M. Sexton, Laurence J. Miller
Summary: This study proposes a new strategy for improving obesity treatment by enhancing the action of the CCK receptor, reducing the likelihood of side effects and toxicity. By identifying positive allosteric modulators (PAMs) with minimal intrinsic agonist activity and studying their mechanisms of action, it is possible to correct abnormal signaling in high-cholesterol environments and develop more effective drugs. The research focuses on compound 1, a weak partial agonist with PAM activity, which enhances CCK signaling without inducing receptor internalization, providing a potential avenue for developing targeted therapies for metabolic regulation.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Article
Pharmacology & Pharmacy
Ke-Ting Pan, I-Hsun Li, Hui-Han Kao, Yi-Hsien Chen, Pei-Xun Zhong, Li-Ting Kao
Summary: This study found that among patients with psoriasis, the use of BZRAs may exacerbate mild symptoms, especially with high doses, while only slightly worsening symptoms in mild cases with low doses. However, low-dose BZRA exposure led to more improvements in psoriasis severity among patients with severe psoriasis. Clinicians should carefully consider the risks and benefits of BZRA usage in psoriasis patients.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Daniela G. G. Dengler, Kaleeckal G. G. Harikumar, Alice Yen, Eduard A. A. Sergienko, Laurence J. J. Miller
Summary: In an effort to develop a drug for obesity, researchers performed a high throughput screening of small molecules to find candidates that can enhance the action of CCK. The study focused on a specific scaffold of tetracyclic molecules and expanded it with commercially available analogs, eliminating off-target effects while retaining its activity as a positive allosteric modulator of CCK1R. These findings provide valuable insights for the future development of potential therapeutic candidates.
Article
Chemistry, Medicinal
Lehao Wu, Jiahua Cui, Chunxiao Zhao, Zeyuan Wang, Jihong Lu, Shaoshun Li, Jinping Jia, Hua Xiao, Yan Zhang
Summary: The study discovered the close association between DMAKO-00 and its derivatives with BB3, with DSO-5a identified as the most potent agonist for BB3. DSO-5a improved glucose tolerance in C57BL/6 mice and glucose homeostasis in diabetic db/db mice through BB3. It was further revealed that DSO-5a upregulated PPAR-γ activity via BB3 through quantitative proteomics. Overall, the study demonstrated that DSO-5a is a potent, selective, and low-brain-penetrating agonist for BB3, and BB3 is a promising treatment target for type 2 diabetes mellitus.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Endocrinology & Metabolism
Hannah Gilliam-Vigh, Tina Jorsal, Jens F. Rehfeld, Jens Pedersen, Steen S. Poulsen, Tina Vilsboll, Filip K. Knop
Summary: The study found that both healthy individuals and patients with type 2 diabetes showed a gradual decrease in CCK mRNA expression and density of CCK cells along the small intestine, with lower levels in the large intestine. There were no significant differences observed in the expression of CCK receptors in the intestines between the two groups.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2021)
Article
Biochemistry & Molecular Biology
Jide Tian, Blake Middleton, Victoria Seunghee Lee, Hye Won Park, Zhixuan Zhang, Bokyoung Kim, Catherine Lowe, Nancy Nguyen, Haoyuan Liu, Ryan S. Beyer, Hannah W. Chao, Ryan Chen, Davis Mai, Karen Anne O'Laco, Min Song, Daniel L. Kaufman
Summary: The expression of gamma-aminobutyric acid receptors in immune cells may have therapeutic potential in diseases like T1D, multiple sclerosis, rheumatoid arthritis, and COVID-19. Specific modulation of GABA(B)-Rs with agonists like lesogaberan shows promise in restoring normoglycemia and improving T1D remission rates in mouse models. The analysis of gene expression databases suggests a common feature of GABA receptors and production/secretion-related genes in immune cells.
Article
Multidisciplinary Sciences
Bryan Faust, Christian B. Billesbolle, Carl-Mikael Suomivuori, Isha Singh, Kaihua Zhang, Nicholas Hoppe, Antonio F. M. Pinto, Jolene K. Diedrich, Yagmur Muftuoglu, Mariusz W. Szkudlinski, Alan Saghatelian, Ron O. Dror, Yifan Cheng, Aashish Manglik
Summary: Thyroid hormones play a crucial role in metabolism, growth, and development. In patients with Graves' disease, autoantibodies can pathologically increase thyroid hormone activity, but how they mimic the function of thyroid-stimulating hormone remains unclear. This study used cryo-electron microscopy to determine the structures of active and inactive thyroid-stimulating hormone receptor (TSHR). The findings reveal that the extracellular domain of TSHR undergoes a conformational change upon activation induced by thyroid-stimulating hormone or activating autoantibodies, providing insights into the mechanism of receptor activation.
Article
Chemistry, Medicinal
Qimeng Yang, Feng Zhou, Xuelin Tang, Jialing Wang, Hui Feng, Wen Jiang, Luofan Jin, Neng Jiang, Yongliang Yuan, Jing Han, Zhiming Yan
Summary: The combined use of gastrointestinal hormones for treating metabolic diseases is receiving increasing attention. A study reported a series of novel GLP-1R/CCK-1R co-agonists and showed that they exerted improved effects on metabolic improvements in obese rodents. These findings suggest a promising combination therapy strategy for treating metabolic disorders.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Medicine, General & Internal
Y. Dauvilliers, E. Mignot, R. del Rio Villegas, Y. Du, E. Hanson, Y. Inoue, H. Kadali, E. Koundourakis, S. Meyer, R. Rogers, T. E. Scammell, S. I. Sheikh, T. Swick, Z. Szakacs, P. von Rosenstiel, J. Wu, H. Zeitz, N. V. Murthy, G. Plazzi, C. von Hehn
Summary: This study found that TAK-994 had a good therapeutic effect in patients with narcolepsy type 1, improving sleepiness and cataplexy symptoms, but it was associated with hepatotoxic effects.
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Jie Yu, Hongtao Zhu, Remigijus Lape, Timo Greiner, Juan Du, Wei Lu, Lucia Sivilotti, Eric Gouaux
Summary: Using electrophysiology and cryo-EM reconstructions, this study investigated the mechanism of partial agonist action on neurotransmitter receptors, revealing new conformational states along the receptor reaction pathway. The results demonstrated that partial agonists can occupy closed channel states bound by agonists, affecting the receptor channel's open probability.
Article
Neurosciences
Alasdair J. Gibb
Summary: NMDA receptors, specifically the triheteromeric structure of GluN1/GluN2B/GluN2D receptors, play fundamental roles in synaptic physiology and have implications for pharmacological research. This study reviews the mechanism of action of drugs targeting allosteric antagonists at these receptors.
Article
Biochemistry & Molecular Biology
Tanusree Chaudhuri, M. V. Hosur
Summary: Epilepsy is a complex neurological disorder and the current drugs used for treatment are ineffective in some cases. Recent studies have found increased expression of alpha 4- and gamma 2-containing synaptic GABARA receptors in patients with refractory epilepsy pathology. Molecular modelling and docking techniques have revealed differences in the structure and ligand-binding efficiency of the alpha 4-containing receptor compared to the alpha 1-containing receptor. These differences may affect the binding of the inhibitory neurotransmitter GABA and the nature of seizures. Furthermore, a steric clash between a specific amino acid residue in the alpha 4-containing receptor and benzodiazapine-type drugs may reduce their binding. These findings provide insights for the development of more effective drugs for epilepsy.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Cardiac & Cardiovascular Systems
Joao Sergio Neves, Marta Borges-Canha, Francisco Vasques-Novoa, Jennifer B. Green, Lawrence A. Leiter, Christopher B. Granger, Davide Carvalho, Adelino Leite-Moreira, Adrian F. Hernandez, Stefano Del Prato, John J. V. McMurray, Joao Pedro Ferreira Md
Summary: This study aimed to evaluate the effects of GLP-1 receptor agonists (GLP-1 RAs) on cardiovascular outcomes in patients with type 2 diabetes (T2D) treated with or without SGLT2 inhibitors. The results showed that GLP-1 RAs reduced cardiovascular events independently of SGLT2 inhibitor use, suggesting that the combination of GLP-1 RAs with SGLT2 inhibitors may further reduce cardiovascular risk.
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
(2023)
Article
Integrative & Complementary Medicine
Matheus Gabriel de Oliveira, Lorrane Kelle da Silva Moreira, Larissa Cordova Turones, Dionys de Souza Almeida, Aline Nazareth Martins, Thiago Levi Silva Oliveira, Vinicius Barreto da Silva, Leonardo Luiz Borges, Elson Alves Costa, Jose Realino de Paula
Summary: This study evaluated the mechanism of action of Hibalactone in its anxiolytic effects through in vivo and in silico analysis. The results showed that Hibalactone activates the benzodiazepine site of the GABA(A) receptor, leading to anxiolytic effects.
JOURNAL OF TRADITIONAL AND COMPLEMENTARY MEDICINE
(2022)
Article
Oncology
Nathalie M. Grob, Roger Schibli, Martin Behe, Thomas L. Mindt
Summary: Several radiolabeled peptides targeting CCK2R-positive cancers have been investigated, with some showing promising tumor-targeting properties. By applying chemical modifications to the peptide Lu-177-PP-F11N, improved radiolabeled peptidomimetics were developed with enhanced tumor uptake and retention, making them promising candidates for imaging and therapy of CCK2R-positive tumors. The use of stable 1,2,3-triazoles as amide bond bioisosteres proved to be a successful strategy in improving the tumor-targeting properties of the peptides.
Article
Pharmacology & Pharmacy
Ahmed Haider, Xiaoyun Deng, Olivia Mastromihalis, Stefanie K. Pfister, Troels E. Jeppesen, Zhiwei Xiao, Vi Pham, Shaofa Sun, Jian Rong, Chunyu Zhao, Jiahui Chen, Yinlong Li, Theresa R. Connors, April T. Davenport, James B. Daunais, Vahid Hosseini, Wenqing Ran, Arthur Christopoulos, Lu Wang, Celine Valant, Steven H. Liang
Summary: This study aimed to develop a suitable M4 PET ligand for the non-invasive visualization of M4 in the brain. The compound 12 was identified as a subtype-selective positive allosteric modulator (PAM) and its radiofluorinated analogue showed moderate specificity in rodent brain sections. However, in non-human primates and humans, the presence of carbachol did not improve the specificity and selectivity of the radioligand.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Biochemistry & Molecular Biology
Sabrina N. Rahman, Daniel A. McNaught-Flores, Yara Huppelschoten, Daniel da Costa Pereira, Arthur Christopoulos, Rob Leurs, Christopher J. Langmead
Summary: The human histamine H3 receptor is expressed in the CNS and regulates the synthesis and release of histamine and neurotransmitters. It is associated with CNS disorders and its isoforms display variations in intracellular loop 3. The mechanisms of biased agonism at these isoforms remain unknown.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Pharmacology & Pharmacy
Ye Jiang, Mahmuda Yeasmin, Arisbel B. Gondin, Arthur Christopoulos, Celine Valant, Wessel A. C. Burger, David M. Thal
Summary: This study investigated the activation of individual G protein subfamilies and downstream signaling pathways of compounds 6A and 7A at the M-2 mAChR. The results showed that M-2 mAChR primarily couples to Galpha(i/o) and Galpha(s), but no Galpha(i) bias was detected for compounds 6A and 7A. This highlights the importance of cellular background in classifying new ligands.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Pharmacology & Pharmacy
Ayame Saito, Sadia Alvi, Celine Valant, Arthur Christopoulos, Simona E. Carbone, Daniel P. Poole
Summary: The enteric nervous system plays a crucial role in regulating gastrointestinal motility. Disrupted enteric nervous system activity can lead to dysmotility. Pharmacological treatment options for dysmotility involve targeting G protein-coupled receptors (GPCRs) expressed by enteric nervous system neurons. Current drugs that target GPCRs for motility disorders have drawbacks such as significant side-effects and a loss of physiological tone. Allosteric modulation of GPCRs, which bind to a distinct site from the endogenous ligand, may provide effective relief from motility disorders while minimizing side-effects.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Endocrinology & Metabolism
Brian P. Cary, Xin Zhang, Jianjun Cao, Rachel M. Johnson, Sarah J. Piper, Elliot J. Gerrard, Denise Wootten, Patrick M. Sexton
Summary: G protein-coupled receptors (GPCRs), particularly the B1 class, play a critical role in maintaining homeostasis and are important drug targets. Recent advances in cryo-electron microscopy have provided valuable insights into the structure and dynamics of these receptors, which contribute to our understanding of their functions.
Review
Pharmacology & Pharmacy
Jo-Anne Baltos, Pablo M. Casillas-Espinosa, Ben Rollo, Karen J. Gregory, Paul J. White, Arthur Christopoulos, Patrick Kwan, Terence J. O'Brien, Lauren T. May
Summary: Epilepsy, a serious neurological condition, affects millions of people worldwide. Current pharmacotherapy only successfully controls seizures in about 70% of epilepsy patients, and many suffer from psychiatric and physical comorbidities. Adenosine, a natural substance, has shown potential as an anti-epileptic agent through its receptor activation. Recent advances have also shown that adenosine receptors can modulate epilepsy-associated comorbidities. This review provides an accessible resource on the use of the adenosine system as a therapeutic target for epilepsy and its associated comorbidities.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Correction
Biochemistry & Molecular Biology
Alexander S. Powers, Vi Pham, Wessel A. C. Burger, Geoff Thompson, Yianni Laloudakis, Nicholas W. Barnes, Patrick M. Sexton, Steven M. Paul, Arthur Christopoulos, David M. Thal, Christian C. Felder, Celine Valant, Ron O. Dror
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Alexander S. Powers, Vi Pham, Wessel A. C. Burger, Geoff Thompson, Yianni Laloudakis, Patrick M. Sexton, Steven M. Paul, Arthur Christopoulos, David M. Thal, Christian C. Felder, Celine Valant, Ron O. Dror
Summary: The selectivity of a drug for target receptors is crucial but challenging when the receptors are similar. Serendipitous discovery of ligands that stimulate target receptors more strongly than closely related receptors provides a solution. This study reveals the structural basis for the efficacy-driven selectivity of xanomeline, a clinical drug candidate, between closely related muscarinic acetylcholine receptors (mAChRs), using atomic-level simulations. The results suggest strategies for rational design of ligands achieving efficacy-driven selectivity for G-protein-coupled receptors.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Pierre Matricon, Anh T. N. Nguyen, Duc Duy Vo, Jo-Anne Baltos, Mariama Jaiteh, Andreas Luttens, Stefanie Kampen, Arthur Christopoulos, Jan Kihlberg, Lauren Therese May, Jens Carlsson
Summary: A structure-based virtual screening approach was used to design subtype-selective ligands for A1 and A2A adenosine receptors. The study identified a non-conserved subpocket in the binding sites that could be exploited to identify A1R selective ligands. Computational screening predicted 20 A1R selective ligands, with 7 of them exhibiting micromolar activities against A1R. Further optimization resulted in antagonists with nanomolar potency and up to 76-fold A1R-selectivity. This study demonstrates the potential of structure-based virtual screening in guiding the discovery and optimization of subtype-selective ligands, enabling the development of safer drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Wessel A. C. Burger, Vi Pham, Ziva Vuckovic, Alexander S. Powers, Jesse I. Mobbs, Yianni Laloudakis, Alisa Glukhova, Denise Wootten, Andrew B. Tobin, Patrick M. Sexton, Steven M. Paul, Christian C. Felder, Radostin Danev, Ron O. Dror, Arthur Christopoulos, Celine Valant, David M. Thal
Summary: The M4 muscarinic acetylcholine receptor is a significant drug target for the treatment of psychosis, cognition, and addiction. The clinical trial of xanomeline has shown promise in improving symptoms and the cryo-EM structure reveals the binding mechanism, providing insight into its complex pharmacology.
NATURE COMMUNICATIONS
(2023)
Meeting Abstract
Pharmacology & Pharmacy
Celine Valant, Alexander Powers, Vi Pham, Wessel Burger, Emma van der Westhuizen, Nicholas Barnes, Steven Paul, Arthur Christopoulos, David Thal, Christian Felder, Ron Dror
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Meeting Abstract
Pharmacology & Pharmacy
Huong Thi Mai Nguyen, Emma van der Westhuizen, Elham Khajehali, Arthur Christopoulos, Celine Valant
BRITISH JOURNAL OF PHARMACOLOGY
(2023)