Article
Chemistry, Medicinal
Dexter C. Davis, Joseph D. Bungard, Sichen Chang, Alice L. Rodriguez, Annie L. Blobaum, Olivier Boutaud, Bruce J. Melancon, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley
Summary: Further optimization of the VU0486321 series of highly selective and CNS-penetrant mGlu1 PAMs identified unique 'molecular switches' on the central aromatic ring that engendered positive cooperativity with multiple mGlu subtypes across the receptor family. This suggests potential therapeutic applications for mGlu1/4/7/8 PAMs and introduces the concept of a GPCR allosteric 'privileged structure'.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Yousuke Yamada, Kristen Gilliland, Zixiu Xiang, Daniel Haymer, Katherine E. Crocker, Matthew T. Loch, Michael L. Schulte, Alice L. Rodriguez, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Bruce J. Melancon
Summary: The letter describes the synthesis and evaluation of two series of dual mGlu(2)/mGlu(3) positive allosteric modulators with moderate mGlu(3) potency and robust mGlu(2) potency. These compounds were shown to effectively modulate mGlu(3)-mediated signaling in central neurons.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Medicine, Research & Experimental
Abdullahi Ibrahim Uba, John Chea, Hannah Hoag, Mariya Hryb, Candice Bui-Linh, Chun Wu
Summary: This study investigates the binding mechanism between PAM CDPPB and mGluR5 using molecular dynamics simulations and molecular switch analysis. The results demonstrate that PAM CDPPB has a strong binding affinity, can induce conformational changes in the receptor, and stabilize the active conformation.
Article
Chemistry, Medicinal
Caitlin N. Kent, Mark G. Fulton, Kaylee J. Stillwell, Jonathan W. Dickerson, Matthew T. Loch, Alice L. Rodriguez, Anna L. Blobaum, Olivier Boutaud, Jerri L. Rook, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley
Summary: A high throughput screen identified a novel, but weak mGlu(4) PAM compound, which was later optimized to deliver a potent compound with good CNS penetration and enantiopreference. The optimized compound displayed robust efficacy in reversing a rodent preclinical Parkinson's disease model.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Carson W. Reed, Alice L. Rodriguez, Jacob J. Kalbfleisch, Mabel Seto, Matthew T. Jenkins, Anna L. Blobaum, Sichen Chang, Craig W. Lindsley, Colleen M. Niswender
Summary: This paper describes a series of negative allosteric modulators (NAMs) of metabotropic glutamate receptor 7 (mGlu7) with a saturable range of activity in inhibiting responses to an orthosteric agonist in two in vitro pharmacological assays. The compounds in this scaffold provide structurally related ligands with differential degrees of receptor blockade, which can be used to understand inhibitory efficacy profiles in native tissue or in vivo.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
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
Biochemistry & Molecular Biology
Anna Stankiewicz, Katarzyna Kaczorowska, Ryszard Bugno, Aneta Koziol, Maria H. Paluchowska, Grzegorz Burnat, Barbara Chruscicka, Paulina Chorobik, Piotr Branski, Joanna M. Wieronska, Beata Duszynska, Andrzej Pilc, Andrzej J. Bojarski
Summary: This study developed a group of 1,2,4-oxadiazole derivatives that exhibited positive allosteric modulatory activity on mGlu(4) receptors. These derivatives were selectively active on mGlu(7) and mGlu(8) receptors and showed anxiolytic- and antipsychotic-like properties.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Nina Treder, Albert Martinez-Pinteno, Natalia Rodriguez, Nestor Arbelo, Santiago Madero, Marta Gomez, Clemente Garcia-Rizo, Sergi Mas, Patricia Gasso, Eduard Parellada, Constanza Moren
Summary: Schizophrenia is a heterogeneous mental disorder that affects approximately 1% of the global population. One of the main pathophysiological theories suggests an imbalance between excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, involving N-methyl-D-aspartate receptors (NMDAr). This imbalance may lead to excessive glutamate storms, dendritic pruning, and cellular stress, including nitrosative stress mediated by nitric oxide (NO). The administration of NMDAr antagonists has been found to increase nitric oxide synthase (NOS) levels in specific brain regions, suggesting a potential target for early treatments. In a murine model, the protein levels of NOS were analyzed in the prefrontal cortex (PFC) and ventral hippocampus (HPC) after ketamine-induced schizophrenia, as well as after treatment with clozapine (CLZ) or JNJ-46356479 (JNJ). The findings suggest a dysregulation of the NOS system following NMDAr antagonist administration, which can be modulated by early CLZ and JNJ treatments.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Daniel H. Wolf, David Zheng, Christian Kohler, Bruce I. Turetsky, Kosha Ruparel, Theodore D. Satterthwaite, Mark A. Elliott, Mary E. March, Alan J. Cross, Mark A. Smith, Stephen R. Zukin, Ruben C. Gur, Raquel E. Gur
Summary: This study found individual differences in symptom reduction with the mGluR2 positive allosteric modulator AZD8529 in schizophrenia patients, as well as improved n-back fMRI activation. Despite no significant overall effects, drug versus placebo effects on brain region activation correlated with symptom reduction, suggesting broader effects across multiple symptom domains.
MOLECULAR PSYCHIATRY
(2022)
Article
Neurosciences
Agata Ploska, Paulina Cieslik, Anna Siekierzycka, Leszek Kalinowski, Joanna M. Wieronska
Summary: The olfactory bulbectomized rat model can be used to study depression and Alzheimer's disease, with neurochemical changes in OBX animals resembling those associated with AD pathology. CDPPB can improve cognitive impairment in the passive avoidance test and partially reverse the changes in nitric oxide synthase expression induced by the lesion.
Article
Biochemistry & Molecular Biology
Lisa Klotz, Ralf Enz
Summary: The study analyzed the expression and localization of mGluR7a and mGluR7b in mouse cochlear wholemounts, finding a presynaptic localization of mGluR7a at inner hair cells (IHCs) and co-localization of mGluR7b with mGluR7a at IHC ribbon synapses. The numbers of mGluR7a and mGluR7b puncta were reduced at higher frequencies and in older animals, indicating potential age and frequency-related changes in the cochlea.
Article
Neurosciences
Chloe Geoffroy, Pierre Paoletti, Laetitia Mony
Summary: NMDA receptors play essential roles in synaptic transmission and plasticity, with both hyper- and hypo-activation being detrimental to neuronal function. Recent developments in NMDAR positive allosteric modulators (PAMs) have provided new insights into potential treatments for conditions like schizophrenia and Alzheimer's disease. Further research is needed to fully understand the physiological effects and therapeutic potential of these modulators in vivo.
JOURNAL OF PHYSIOLOGY-LONDON
(2022)
Article
Neurosciences
Imane Frouni, Cynthia Kwan, Dominique Bedard, Woojin Kang, Adjia Hamadjida, Stephen G. Nuara, Jim C. Gourdon, Philippe Huot
Summary: The study found that ADX-88178 has anti-parkinsonian and anti-dyskinetic effects, but may exacerbate dopaminergic psychosis. Further research is needed to evaluate the adverse effects of mGlu(4) PAMs on PD psychosis.
PSYCHOPHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Corinna Schuess, Oanh Vu, Nigam M. Mishra, Iain R. Tough, Yu Du, Jan Stichel, Helen M. Cox, C. David Weaver, Jens Meiler, Kyle A. Emmitte, Annette G. Beck-Sickinger
Summary: In this study, a novel positive allosteric modulator (PAM) VU0506013 targeting the Y4R receptor was identified. It showed nanomolar affinity and selectivity towards the Y4R and has potential for anti-obesity research.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Neurosciences
Kimberly M. Holter, Alex D. Lekander, Christina M. LaValley, Elizabeth G. Bedingham, Bethany E. Pierce, L. Paul Sands, Craig W. Lindsley, Carrie K. Jones, Robert W. Gould
Summary: Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor subtype 5 (mGlu(5)) have shown anxiolytic and antidepressant effects, but concerns remain about potential adverse effects. Partial mGlu(5) NAMs, with submaximal levels of blockade, may have a broader therapeutic index than full mGlu(5) NAMs. Studies comparing M-5MPEP and VU0424238 found differences in their effects on sleep, cognition, and brain function, supporting the development of partial mGlu(5) NAMs.
FRONTIERS IN NEUROSCIENCE
(2021)
Article
Chemistry, Medicinal
Pedro M. Garcia-Barrantes, Hyekyung P. Cho, Colleen M. Niswender, Frank W. Byers, Charles W. Locuson, Anna L. Blobaum, Zixiu Xiang, Jerri M. Rook, P. Jeffrey Conn, Craig W. Lindsley
JOURNAL OF MEDICINAL CHEMISTRY
(2015)
Article
Chemistry, Medicinal
Susana Conde-Ceide, Carlos M. Martinez-Viturro, Jesus Alcazar, Pedro M. Garcia-Barrantes, Hilde Lavreysen, Claire Mackie, Paige N. Vinson, Jerri M. Rook, Thomas M. Bridges, J. Scott Daniels, Anton Megens, Xavier Langlois, Wilhelmus H. Drinkenburg, Abdellah Ahnaou, Colleen M. Niswender, Carrie K. Jones, Gregor J. Macdonald, Thomas Steckler, P. Jeffrey Conn, Shaun R. Stauffer, Jose Manuel Bartolome-Nebreda, Craig W. Lindsley
ACS MEDICINAL CHEMISTRY LETTERS
(2015)
Article
Biochemistry & Molecular Biology
Darren W. Engers, Anna L. Blobaum, Rocco D. Gogliotti, Yiu-Yin Cheung, James M. Salovich, Pedro M. Garcia-Barrantes, J. Scott Daniels, Ryan Morrison, Carrie K. Jones, Matthew G. Soars, Xiaoliang Zhuo, Jeremy Hurley, John E. Macor, Joanne J. Bronson, P. Jeffrey Conn, Craig W. Lindsley, Colleen M. Niswender, Corey R. Hopkins
ACS CHEMICAL NEUROSCIENCE
(2016)
Article
Chemistry, Medicinal
Pedro M. Garcia-Barrantes, Hyekyung P. Cho, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2016)
Article
Chemistry, Medicinal
Pedro M. Garcia-Barrantes, Hyekyung P. Cho, Adam M. Metts, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2016)
Article
Chemistry, Medicinal
Pedro M. Garcia-Barrantes, Hyekyung P. Cho, Tahj M. Starr, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2016)
Article
Chemistry, Medicinal
Joseph D. Panarese, Hykeyung P. Cho, Jeffrey J. Adams, Kellie D. Nance, Pedro M. Garcia-Barrantes, Sichen Chang, Ryan D. Morrison, Anna L. Blobaum, Colleen M. Niswender, Shaun R. Stauffer, P. Jeffrey Conn, Craig W. Lindsley
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2016)
Article
Chemistry, Medicinal
Rocco D. Gogliotti, Darren W. Engers, Pedro M. Garcia-Barrantes, Joseph D. Panarese, Patrick R. Gentry, Anna L. Blobaum, Ryan D. Morrison, J. Scott Daniels, Analisa D. Thompson, Carrie K. Jones, P. Jeffrey Conn, Colleen M. Niswender, Craig W. Lindsley, Corey R. Hopkins
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2016)
Article
Chemistry, Organic
Pedro M. Garcia-Barrantes, Craig W. Lindsley
Article
Biochemistry & Molecular Biology
Jerri M. Rook, Jeanette L. Bertron, Hyekyung P. Cho, Pedro M. Garcia-Barrantes, Sean P. Moran, James T. Maksymetz, Kellie D. Nance, Jonathan W. Dickerson, Daniel H. Remke, Sichen Chang, Joel M. Harp, Anna L. Blobaum, Colleen M. Niswender, Carrie K. Jones, Shaun R. Stauffer, P. Jeffrey Conn, Craig W. Lindsley
ACS CHEMICAL NEUROSCIENCE
(2018)
Article
Chemistry, Medicinal
Jeanette L. Bertron, Hyekyung P. Cho, Pedro M. Garcia-Barrantes, Joseph D. Panarese, James M. Salovich, Kellie D. Nance, Darren W. Engers, Jerri M. Rook, Anna L. Blobaum, Colleen M. Niswender, Shaun R. Stauffer, P. Jeffrey Conn, Craig W. Lindsley
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2018)
Article
Biochemistry & Molecular Biology
Hyekyung P. Cho, Pedro M. Garcia-Barrantes, John T. Brogan, Corey R. Hopkins, Colleen M. Niswender, Alice L. Rodriguez, Daryl F. Venable, Ryan D. Morrison, Michael Bubser, J. Scott Daniels, Carrie K. Jones, P. Jeffrey Conn, Craig W. Lindsley
ACS CHEMICAL BIOLOGY
(2014)
Article
Biochemistry & Molecular Biology
Samantha E. Yohn, Daniel J. Foster, Dan P. Covey, Mark S. Moehle, Jordan Galbraith, Pedro M. Garcia-Barrantes, Hyekyung P. Cho, Michael Bubser, Anna L. Blobaum, Max E. Joffe, Joseph F. Cheer, Carrie K. Jones, Craig W. Lindsley, P. Jeffrey Conn
MOLECULAR PSYCHIATRY
(2020)
Article
Biochemistry & Molecular Biology
Jerri M. Rook, Masahito Abe, Hyekyung P. Cho, Kellie D. Nance, Vincent B. Luscombe, Jeffrey J. Adams, Jonathan W. Dickerson, Daniel H. Remke, Pedro M. Garcia-Barrantes, Darren W. Engers, Julie L. Engers, Sichen Chang, Jarrett J. Foster, Anna L. Blobaum, Colleen M. Niswender, Carrie K. Jones, P. Jeffrey Conn, Craig W. Lindsley
ACS CHEMICAL NEUROSCIENCE
(2017)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)