Article
Chemistry, Medicinal
Madeline F. Long, Rory A. Capstick, Paul K. Spearing, Julie L. Engers, Alison R. Gregro, Sean R. Bollinger, Sichen Chang, Vincent B. Luscombe, Alice L. Rodriguez, Hyekyung P. Cho, Colleen M. Niswender, Thomas M. Bridges, P. Jeffrey Conn, Craig W. Lindsley, Darren W. Engers, Kayla J. Temple
Summary: The Letter details efforts to develop novel tricyclic M-4 PAM scaffolds with improved pharmacological properties. A tie-back strategy was employed to replace the core structure, leading to the discovery of two novel tricyclic cores with low nanomolar potency against the human M-4 receptor.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Neurosciences
Henry S. Lange, Joshua D. Vardigan, Christopher E. Cannon, Vanita Puri, Darrell A. Henze, Jason M. Uslaner
Summary: Alzheimer's disease is a profoundly debilitating neurodegenerative disorder, and Compound 24 has shown potential therapeutic effects in non-human primates, reducing behavioral disturbances and enhancing cognitive function.
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
Neurosciences
Laura B. Teal, Michael Bubser, Edith Duncan, Robert W. Gould, Craig W. Lindsley, Carrie K. Jones
Summary: Recent evidence suggests that inhibition of the M5 muscarinic acetylcholine receptor (mAChR) may provide a novel non-opioid mechanism for the treatment of opioid use disorder (OUD). In this study, the effects of the M5 negative allosteric modulator (NAM) VU6008667 on oxycodone self-administration and reinstatement behaviors were evaluated. The results showed that VU6008667 decreased oxycodone self-administration and attenuated cue-induced reinstatement of lever pressing, while having minimal effects on other behaviors.
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
Physiology
Kensuke Hirose, Yuka Nakaya, Kohei Kitano, Yasuhiko Saito, Ryosuke Kaneko, Yuchio Yanagawa, Kiyofumi Yamamoto, Tetsuo Shirakawa, Masayuki Kobayashi
Summary: The study revealed that NAc MSNs and ChNs are differentially regulated by excitatory projections from the IC and mPFC, and these corticoaccumbal excitatory inputs are modulated by M-1 receptor activation.
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2021)
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
Immunology
Tehila Mizrachi, Oshrit Marsha, Karen Brusin, Yael Ben-David, Ganesh A. Thakur, Adi Vaknin-Dembinsky, Millet Treinin, Talma Brenner
Summary: GAT107, an ago-PAM of alpha 7 nAChR, can significantly reduce disease severity and neuroinflammation in EAE by activating the receptor, leading to decreased pro-inflammatory cytokine production and increased anti-inflammatory cytokine IL-10. It also alters the expression of immune cell markers and directly activates alpha 7 nAChR in immune cells of MS patients and healthy donors.
JOURNAL OF NEUROINFLAMMATION
(2021)
Article
Pharmacology & Pharmacy
Khaled S. Abd-Elrahman, Shaarika Sarasija, Tash-Lynn L. Colson, Stephen S. G. Ferguson
Summary: This study suggests that using M1 mAChR positive allosteric modulator (PAM) VU0486846 can improve cognitive function and reduce Aβ oligomer production in female mice with Alzheimer's disease (AD). This treatment approach could be a viable disease-modifying strategy to slow down the progression of AD in women.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
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
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
Cell Biology
Lisa M. Henkel, Svenja Kankowski, Thiemo M. Moellenkamp, Nadine J. Smandzich, Sigrid Schwarz, Alessio Di Fonzo, Gudrun Goehring, Guenter Hoeglinger, Florian Wegner
Summary: In this study, induced pluripotent stem cells (iPSCs) were generated and differentiated into medium spiny neurons (MSNs) in the striatum from patients with probable MSA-P and healthy controls. The MSNs derived from MSA-P patients showed significantly elevated release and neuronal distribution of alpha-synuclein, as well as hypoexcitability compared to healthy controls. These findings suggest that hypoexcitable neurons in the striatum of MSA-P patients contribute to the pathological burden of alpha-synuclein and facilitate disease progression.
Article
Biochemistry & Molecular Biology
Russell Dahl, Amanda C. Moore, Caitlynn Knight, Colleen Mauger, Hua Zhang, Gary E. Schiltz, Wendy A. Koss, Ilya Bezprozvanny
Summary: Alzheimer's disease (AD) is an irreversible neurodegenerative disease that affects millions of people worldwide. Dysregulated neuronal calcium (Ca2+) signaling has been identified as a key pathogenic event in addition to the amyloid pathway. This study developed a novel SERCA PAM agent, compound NDC-1173, and demonstrated its potential as a disease-modifying agent in AD using behavioral studies and evaluation of gene expression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Chrysa Malosh, Mark Turlington, Thomas M. Bridges, Jerri M. Rook, Meredith J. Noetzel, Paige N. Vinson, Thomas Steckler, Hilde Lavreysen, Claire Mackie, Jose M. Bartolome-Nebreda, Susana Conde-Ceide, Carlos M. Martinez-Viturro, Maria Piedrafita, M. Rosa Sanchez-Casado, Gregor J. Macdonald, J. Scott Daniels, Carrie K. Jones, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Shaun R. Stauffer
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2015)
Article
Chemistry, Organic
Savannah Jordan, Samuel A. Starks, Michael F. Whatley, Mark Turlington
Article
Chemistry, Organic
Danielle N. Penk, Nathan A. Robinson, Harrison M. Hill, Mark Turlington
TETRAHEDRON LETTERS
(2017)
Article
Chemistry, Medicinal
Mark Turlington, Aspen Chun, Sakshi Tomar, Aimee Eggler, Valerie Grum-Tokars, Jon Jacobs, J. Scott Daniels, Eric Dawson, Adrian Saldanha, Peter Chase, Yahira M. Baez-Santos, Craig W. Lindsley, Peter Hodder, Andrew D. Mesecar, Shaun R. Stauffer
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2013)
Article
Chemistry, Medicinal
Mark Turlington, Meredith J. Noetzel, Thomas M. Bridges, Paige N. Vinson, Thomas Steckler, Hilde Lavreysen, Claire Mackie, Jose M. Bartolome-Nebreda, Susana Conde-Ceide, Han Min Tong, Gregor J. Macdonald, J. Scott Daniels, Carrie K. Jones, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Shaun R. Stauffer
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2014)
Article
Chemistry, Multidisciplinary
Michael L. Schulte, Mark L. Turlington, Sharangdhar S. Phatak, Joel M. Harp, Shaun R. Stauffer, Craig W. Lindsley
CHEMISTRY-A EUROPEAN JOURNAL
(2013)
Article
Chemistry, Medicinal
Mark Turlington, Meredith J. Noetzel, Aspen Chun, Ya Zhou, Rocco D. Gogliotti, Elizabeth D. Nguyen, Karen J. Gregory, Paige N. Vinson, Jerri M. Rook, Kiran K. Gogi, Zixiu Xiang, Thomas M. Bridges, J. Scott Daniels, Carrie Jones, Colleen M. Niswender, Jens Meiler, P. Jeffrey Conn, Craig W. Lindsley, Shaun R. Stauffer
JOURNAL OF MEDICINAL CHEMISTRY
(2013)
Article
Chemistry, Medicinal
Jon Jacobs, Valerie Grum-Tokars, Ya Zhou, Mark Turlington, S. Adrian Saldanha, Peter Chase, Aimee Eggler, Eric S. Dawson, Yahira M. Baez-Santos, Sakshi Tomar, Anna M. Mielech, Susan C. Baker, Craig W. Lindsley, Peter Hodder, Andrew Mesecar, Shaun R. Stauffer
JOURNAL OF MEDICINAL CHEMISTRY
(2013)
Article
Chemistry, Medicinal
Mark Turlington, Chrysa Malosh, Jon Jacobs, Jason T. Manka, Meredith J. Noetzel, Paige N. Vinson, Satyawan Jadhav, Elizabeth J. Herman, Hilde Lavreysen, Claire Mackie, Jose M. Bartolome-Nebreda, Susana Conde-Ceide, M. Luz Martin-Martin, Han Min Tong, Silvia Lopez, Gregor J. MacDonald, Thomas Steckler, J. Scott Daniels, C. David Weaver, Colleen M. Niswender, Carrie K. Jones, P. Jeffrey Conn, Craig W. Lindsley, Shaun R. Stauffer
JOURNAL OF MEDICINAL CHEMISTRY
(2014)
Article
Chemistry, Organic
Gary W. Breton, Mark Turlington
TETRAHEDRON LETTERS
(2014)
Article
Chemistry, Multidisciplinary
Jake E. Doiron, Christina A. Le, Britton K. Ody, Jonathon B. Brace, Savannah J. Post, Nathan L. Thacker, Harrison M. Hill, Gary W. Breton, Matthew J. Mulder, Sichen Chang, Thomas M. Bridges, Liping Tang, Wei Wang, Steven M. Rowe, Stephen G. Aller, Mark Turlington
CHEMISTRY-A EUROPEAN JOURNAL
(2019)
Article
Chemistry, Medicinal
Jake E. Doiron, Christina A. Le, John Bacsa, Gary W. Breton, Kenneth L. Martin, Stephen G. Aller, Mark L. Turlington
Article
Chemistry, Organic
Charles S. Jolly, Emma Kochanowski, Cayden J. Dodd, Savannah J. Post, Harrison M. Hill, Mark Turlington
Summary: The stereoselective synthesis of terminal bromosubstituted propargylamines via in situ generation of lithium bromoacetylide from 1,2-dibromoethene and addition to Ellman chiral N-tert-butanesulfinyl aldimines is reported. The method allows for the direct use of the prepared propargylamines in Cadiot-Chodkiewicz coupling to produce functionalized diynes, increasing the structural diversity of these compounds.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Polymer Science
Erin E. E. Ramey, Elizabeth L. L. Whitman, Cole E. E. Buller, James R. R. Tucker, Charles S. S. Jolly, Kjersti G. G. Oberle, Austin J. J. Becksvoort, Mark Turlington, Christopher R. R. Turlington
Summary: Biodegradable polymers are important for reducing the impact of plastic waste on the environment. The development of organocatalytic ring-opening polymerization has enabled the synthesis of new types of biodegradable polymers. This research article presents the first example of an oxygen atom transfer reagent attached to a biodegradable polymer backbone. The polymer demonstrates the ability to engage in an oxygen atom transfer reaction with a substrate.
Article
Pharmacology & Pharmacy
Anna L. Blobaum, Thomas M. Bridges, Frank W. Byers, Mark L. Turlington, Margrith E. Mattmann, Ryan D. Morrison, Claire Mackie, Hilde Lavreysen, Jose M. Bartolome, Gregor J. MacDonald, Thomas Steckler, Carrie K. Jones, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Shaun R. Stauffer, J. Scott Daniels
DRUG METABOLISM AND DISPOSITION
(2013)