Article
Multidisciplinary Sciences
Miriam Scarpa, Colin Molloy, Laura Jenkins, Bethany Strellis, Rebecca F. Budgett, Sarah Hesse, Louis Dwomoh, Sara Marsango, Gonzalo S. Tejeda, Mario Rossi, Zeshan Ahmed, Graeme Milligan, Brian D. Hudson, Andrew B. Tobin, Sophie J. Bradley
Summary: Current treatments for neurodegenerative diseases like Alzheimer's disease have shown limited effectiveness, but activating the M1 receptor could potentially restore memory and slow disease progression. Recent research suggests that minimizing adverse reactions associated with M1 receptor activation can be achieved by ensuring proper phosphorylation and arrestin-dependent signaling. This approach shows promise for developing next-generation M1 receptor ligands with reduced side effects and improved neuroprotection.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Pharmacology & Pharmacy
Alena Randakova, Jan Jakubik
Summary: Cholinergic signalling disruption through muscarinic receptors is linked to various pathologies, with potential therapeutic benefits found in selective muscarinic agonists. The identical orthosteric binding site across all muscarinic receptor subtypes makes the development of affinity-based selective agonists nearly impossible. Functionally selective and biased agonists show promise for selectively targeting individual muscarinic receptor subtypes.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Chemistry, Medicinal
Manuela Jorg, Emma T. van der Westhuizen, Yao Lu, K. H. Christopher Choy, David M. Shackleford, Elham Khajehali, Andrew B. Tobin, David M. Thal, Ben Capuano, Arthur Christopoulos, Celine Valant, Peter J. Scammells
Summary: The synthesis and comprehensive pharmacological evaluation of M4 mAChR PAMs structurally related to 1e, Me-C-c, [11C]MK-6884 and [18F]12 were reported. Small structural changes to the PAMs resulted in significant differences in baseline, potency, and maximum effect measures in cAMP assays compared to the endogenous ligand acetylcholine (ACh). The discovery of novel PAMs with improved allosteric properties, 6k and 6l, and their ability to cross the blood-brain barrier make them more suitable for future preclinical assessment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Huong T. M. Nguyen, Emma T. van der Westhuizen, Christopher J. Langmead, Andrew B. Tobin, Patrick M. Sexton, Arthur Christopoulos, Celine Valant
Summary: This review focuses on the drug discovery of M-1 receptor for the treatment of Alzheimer's disease and schizophrenia. Despite some progress, only a few drugs have reached clinical trials due to cholinergic adverse effects.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Yaopeng Zhao, Jixia Wang, Tao Hou, Yancheng Yu, Han Zhou, Yang Han, Junxiang Cheng, Yanfang Liu, Chaoran Wang, Long Chen, Xinmiao Liang
Summary: A series of 2-(2,2-diarylethyl)-cyclamine derivatives were designed and synthesized as M3 mAChR antagonists, showing excellent selectivity and antagonistic activity. These novel compounds have the potential to be candidates for COPD drug development.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Manuela Jorg, Elham Khajehali, Emma T. van der Westhuizen, K. H. C. Choy, David M. Shackleford, Andrew B. Tobin, Patrick M. Sexton, Celine Valant, Ben Capuano, Arthur Christopoulos, Peter J. Scammells
Summary: This study investigated the structure-activity relationships of 4-phenylpyridin-2-one and 6-phenylpyrimidin-4-one M(1)muscarinic acetylcholine receptor positive allosteric modulators (PAMs), showing that modifications to the analogues result in nuanced effects on the allosteric properties. The research also found that despite primarily acting as affinity modulators, the PAMs displayed different pharmacological properties across the two cellular assays. The novel PAM7 was identified as a potential lead candidate for further development due to its lower BBB permeability and improved exposure in the periphery compared to lead2.
Article
Pharmacology & Pharmacy
Risa Okimoto, Katsutoshi Ino, Kenichiro Ishizu, Hajime Takamatsu, Kazuyuki Sakamoto, Hironori Yuyama, Hideyoshi Fuji, Akiyoshi Someya, Akiyoshi Ohtake, Takao Ishigami, Noriyuki Masuda, Masahiro Takeda, Shunichi Kajioka, Naoki Yoshimura
Summary: The novel M-3 receptor positive allosteric modulator ASP8302 enhances human M-3 receptor activation by interacting with a residue distinct from reported allosteric sites, suggesting not only a novel allosteric site of M-3 receptors but also potential application in diseases caused by insufficient M-3 receptor activation. This finding provides significant insight into further research on the allosteric modulation mechanism of M-3 and other muscarinic receptors.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2021)
Article
Multidisciplinary Sciences
Seyed A. Hassani, Adam Neumann, Jason Russell, Carrie K. Jones, Thilo Womelsdorf
Summary: The positive allosteric modulator of M1 mAChRs, VU0453595, enhances cognitive flexibility by improving flexible learning performance, reducing latency inhibition, and reducing response perseveration. However, the acetylcholinesterase inhibitor donepezil only improves attention during visual search without affecting cognitive flexibility. Therefore, M1 mAChR positive allosteric modulators have versatile applications in enhancing cognitive flexibility.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Wessel A. C. Burger, Patrick R. Gentry, Alice E. Berizzi, Ziva Vuckovic, Emma T. van der Westhuizen, Geoff Thompson, Mahmuda Yeasmin, Craig W. Lindsley, Patrick M. Sexton, Christopher J. Langmead, Andrew B. Tobin, Arthur Christopoulos, Celine Valant, David M. Thal
Summary: The potential binding site for ML375 in M-5 mAChR was identified at the interface of TMs 2-4, aiding in the development of novel selective M-5 mAChR modulators.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Chemistry, Medicinal
Paul K. Spearing, Hyekyung P. Cho, Vincent B. Luscombe, Anna L. Blobaum, Olivier Boutaud, Darren W. Engers, Alice L. Rodriguez, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Aaron M. Bender
Summary: This letter describes the synthesis and optimization of a series of heteroaryl-pyrrolidinone positive allosteric modulators (PAMs) for the muscarinic acetylcholine receptor M-1 (mAChR M-1). Through continued optimization, two compounds, 8b (VU6005610) and 20a (VU6005852), were found to have robust selectivity for the M-1 mAChR with no agonism. Additionally, compound 8b showed high brain exposure in a rodent IV cassette model.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
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)
Article
Multidisciplinary Sciences
Roger M. Pallares, David Faulkner, Dahlia D. An, Solene Hebert, Alex Loguinov, Michael Proctor, Jonathan A. Villalobos, Kathleen A. Bjornstad, Chris J. Rosen, Christopher Vulpe, Rebecca J. Abergel
Summary: Lanthanides, a group of critical elements widely used in various industries, have been found to potentially impact human health. This study used a functional toxicogenomics approach in baker's yeast to assess the toxicity mechanisms of lanthanides, revealing different trends and effects on cellular responses. The research highlighted the disruption of vesicle-mediated transport and biosynthetic pathways as key functions affected by lanthanides, with implications for potential targeting of human orthologs by these elements.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Gastroenterology & Hepatology
Yoko Igarashi-Hisayoshi, Eikichi Ihara, Xiaopeng Bai, Chika Higashi, Hiroko Ikeda, Yoshimasa Tanaka, Mayumi Hirano, Haruei Ogino, Takatoshi Chinen, Yasushi Taguchi, Yoshihiro Ogawa
Summary: This study investigated the region-specific role of the M-3 receptor in gastrointestinal motility using a novel positive allosteric modulator (PAM-369). The results showed that PAM-369 selectively potentiated the M-3 receptor without agonistic or antagonistic activity and increased small intestinal transit in mice. However, it had no effect on colonic transit. This study provides the first direct evidence of the different functional roles of the M-3 receptor between the small intestine and colon.
DIGESTIVE DISEASES AND SCIENCES
(2023)
Article
Multidisciplinary Sciences
Elodie Caudal, Anne Friedrich, Arthur Jallet, Marion Garin, Jing Hou, Joseph Schacherer
Summary: The same mutation can lead to different phenotypic outcomes in different genetic backgrounds. By studying 39 natural isolates of Saccharomyces cerevisiae, it was found that 15% of genes exhibited significant fitness changes when impacted by a gene loss-of-function mutation. Genes related to mitochondrial function were overrepresented and showed potential rewiring effects with other genes involved in transcription, chromatin remodeling, and nuclear-cytoplasmic transport. These effects are likely influenced by both genetic background and environment.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemical Research Methods
David G. Nickens, Matthew L. Bochman
Summary: DNA helicases play a crucial role in nucleic acid transactions and genome integrity. Research has shown that the PIF1 (Pif1 and Rrm3) and RecQ (Hrq1 and Sgs1) family helicases exhibit genetic and biochemical interactions in vivo, affecting genome integrity pathways and telomerase activity.
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)
Review
Pharmacology & Pharmacy
Maleesha Ubhayarathna, Christopher J. Langmead, Natalie A. Diepenhorst, Gregory D. Stewart
Summary: Substance use disorder is a chronic condition with limited treatment options. The serotonin 2C receptor shows potential for the treatment of SUD, and research on psychedelics has also focused on this receptor. New studies provide a basis for further exploration.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Pharmacology & Pharmacy
Yao Lu, Cassandra J. Hatzipantelis, Christopher J. Langmead, Gregory D. Stewart
Summary: Schizophrenia treatment currently relies on outdated science, and targeting dopamine receptors has limited efficacy and side effects. Non-dopaminergic GPCR-targeting drugs show promise but have not yet been successfully developed for clinical use. Recent attention has focused on non-dopaminergic GPCR-targeting drugs, which have demonstrated efficacy in certain symptoms of schizophrenia.
BRITISH JOURNAL OF PHARMACOLOGY
(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)