310 results on '"Colleen M. Niswender"'
Search Results
2. mGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits
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James Maksymetz, Nellie E. Byun, Deborah J. Luessen, Brianna Li, Robert L. Barry, John C. Gore, Colleen M. Niswender, Craig W. Lindsley, Max E. Joffe, and P. Jeffrey Conn
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metabotropic glutamate receptor ,mGlu1 ,prefrontal cortex ,inhibitory transmission ,somatostatin interneurons ,excitation-inhibition balance ,Biology (General) ,QH301-705.5 - Abstract
Summary: Evidence for prefrontal cortical (PFC) GABAergic dysfunction is one of the most consistent findings in schizophrenia and may contribute to cognitive deficits. Recent studies suggest that the mGlu1 subtype of metabotropic glutamate receptor regulates cortical inhibition; however, understanding the mechanisms through which mGlu1 positive allosteric modulators (PAMs) regulate PFC microcircuit function and cognition is essential for advancing these potential therapeutics toward the clinic. We report a series of electrophysiology, optogenetic, pharmacological magnetic resonance imaging, and animal behavior studies demonstrating that activation of mGlu1 receptors increases inhibitory transmission in the prelimbic PFC by selective excitation of somatostatin-expressing interneurons (SST-INs). An mGlu1 PAM reverses cortical hyperactivity and concomitant cognitive deficits induced by N-methyl-d-aspartate (NMDA) receptor antagonists. Using in vivo optogenetics, we show that prelimbic SST-INs are necessary for mGlu1 PAM efficacy. Collectively, these findings suggest that mGlu1 PAMs could reverse cortical GABAergic deficits and exhibit efficacy in treating cognitive dysfunction in schizophrenia.
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- 2021
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3. Evaluation of Synthetic Cytochrome P450-Mimetic Metalloporphyrins To Facilitate 'Biomimetic' Biotransformation of a Series of mGlu5 Allosteric Ligands
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Christopher C. Presley, Charles K. Perry, Elizabeth S. Childress, Matthew J. Mulder, Vincent B. Luscombe, Alice L. Rodriguez, Colleen M. Niswender, P. Jeffrey Conn, and Craig W. Lindsley
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Chemistry ,QD1-999 - Published
- 2019
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4. A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes
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Nicole M. Fisher, Aqeela AlHashim, Aditi B. Buch, Hana Badivuku, Manar M. Samman, Kelly M. Weiss, Gabriela I. Cestero, Mark D. Does, Jerri M. Rook, Craig W. Lindsley, P. Jeffrey Conn, Rocco G. Gogliotti, and Colleen M. Niswender
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Neuroscience ,Medicine - Abstract
The metabotropic glutamate receptor 7 (mGlu7) is a G protein–coupled receptor that has been recently linked to neurodevelopmental disorders. This association is supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity disorder, and severe developmental delay. One GRM7 mutation previously reported in 2 patients results in a single amino acid change, I154T, within the mGlu7 ligand-binding domain. Here, we report 2 new patients with this mutation who present with severe developmental delay and epilepsy. Functional studies of the mGlu7-I154T mutant reveal that this substitution resulted in significant loss of mGlu7 protein expression in HEK293A cells and in mice. We show that this occurred posttranscriptionally at the level of protein expression and trafficking. Similar to mGlu7–global KO mice, mGlu7-I154T animals exhibited reduced motor coordination, deficits in contextual fear learning, and seizures. This provides functional evidence that a disease-associated mutation affecting the mGlu7 receptor was sufficient to cause neurological dysfunction in mice and further validates GRM7 as a disease-causing gene in the human population.
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- 2021
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5. Corrigendum: Metabotropic Glutamate Receptor 7: A New Therapeutic Target in Neurodevelopmental Disorders
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Nicole M. Fisher, Mabel Seto, Craig W. Lindsley, and Colleen M. Niswender
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Neurodevelopmental disorder ,ASD ,Rett syndrome ,mGlu7 ,GRM7 ,allosteric modulator ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2018
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6. Metabotropic Glutamate Receptor 7: A New Therapeutic Target in Neurodevelopmental Disorders
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Nicole M. Fisher, Mabel Seto, Craig W. Lindsley, and Colleen M. Niswender
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neurodevelopmental disorder ,ASD ,Rett syndrome ,mGlu7 ,GRM7 ,allosteric modulator ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Neurodevelopmental disorders (NDDs) are characterized by a wide range of symptoms including delayed speech, intellectual disability, motor dysfunction, social deficits, breathing problems, structural abnormalities, and epilepsy. Unfortunately, current treatment strategies are limited and innovative new approaches are sorely needed to address these complex diseases. The metabotropic glutamate receptors are a class of G protein-coupled receptors that act to modulate neurotransmission across many brain structures. They have shown great promise as drug targets for numerous neurological and psychiatric diseases. Moreover, the development of subtype-selective allosteric modulators has allowed detailed studies of each receptor subtype. Here, we focus on the metabotropic glutamate receptor 7 (mGlu7) as a potential therapeutic target for NDDs. mGlu7 is expressed widely throughout the brain in regions that correspond to the symptom domains listed above and has established roles in synaptic physiology and behavior. Single nucleotide polymorphisms and mutations in the GRM7 gene have been associated with idiopathic autism and other NDDs in patients. In rodent models, existing literature suggests that decreased mGlu7 expression and/or function may lead to symptoms that overlap with those of NDDs. Furthermore, potentiation of mGlu7 activity has shown efficacy in a mouse model of Rett syndrome. In this review, we summarize current findings that provide rationale for the continued development of mGlu7 modulators as potential therapeutics.
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- 2018
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7. Optimized Administration of the M
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Jakub, Cikowski, Calista, Holt, Bright, Arthur, Mackenzie, Smith, Sonia, Gonzalez, Craig W, Lindsley, Colleen M, Niswender, and Rocco G, Gogliotti
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Mice, Knockout ,Pyridazines ,Disease Models, Animal ,Mice ,Methyl-CpG-Binding Protein 2 ,Cholinergic Agents ,Rett Syndrome ,Animals ,Thiophenes - Abstract
Hypofunction of cholinergic circuits and diminished cholinergic tone have been associated with the neurodevelopmental disorder Rett syndrome (RTT). Specifically, deletion of
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- 2023
8. Glial Cell Development is Changed by Genetic Overexpression of MeCP2 in a Pitt-Hopkins Syndrome Mouse Model
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Geanne A. Freitas, Sheryl Anne D. Vermudez, Vaishnavi M. Bavadekar, Rocco Gogliotti, and Colleen M. Niswender
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- 2023
9. Profiling Context-Dependent Activity of Allosteric Modulators at mGlu7
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Xia Lei, Alice Rodriguez, and Colleen M. Niswender
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- 2023
10. Optimized Administration of the M4 PAM VU0467154 Demonstrates Broad Efficacy, but Limited Effective Concentrations in Mecp2+/– Mice
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Jakub Cikowski, Calista Holt, Bright Arthur, Mackenzie Smith, Sonia Gonzalez, Craig W. Lindsley, Colleen M. Niswender, and Rocco G. Gogliotti
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Physiology ,Cognitive Neuroscience ,Cell Biology ,General Medicine ,Biochemistry - Published
- 2022
11. Clinical and Preclinical Evidence for M1 Muscarinic Acetylcholine Receptor Potentiation as a Therapeutic Approach for Rett Syndrome
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Mackenzie Smith, Bright Arthur, Jakub Cikowski, Calista Holt, Sonia Gonzalez, Nicole M. Fisher, Sheryl Anne D. Vermudez, Craig W. Lindsley, Colleen M. Niswender, and Rocco G. Gogliotti
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Pharmacology ,Pharmacology (medical) ,Neurology (clinical) - Abstract
SummaryRett syndrome (RTT) is a neurodevelopmental disorder that is characterized by developmental regression, loss of communicative ability, stereotyped hand wringing, cognitive impairment, and central apneas, among many other symptoms. RTT is caused by loss-of-function mutations in a methyl-reader known as methyl-CpG-binding protein 2 (MeCP2), a protein that links epigenetic changes on DNA to larger chromatin structure. Historically, target identification for RTT has relied heavily on Mecp2 knockout mice; however, we recently adopted the alternative approach of performing transcriptional profiling in autopsy samples from RTT patients. Through this mechanism, we identified muscarinic acetylcholine receptors (mAChRs) as potential therapeutic targets. Here, we characterized a cohort of 40 temporal cortex samples from individuals with RTT and quantified significantly decreased levels of the M1, M2, M3, and M5 mAChRs subtypes relative to neurotypical controls. Of these four subtypes, M1 expression demonstrated a linear relationship with MeCP2 expression, such that M1 levels were only diminished in contexts where MeCP2 was also significantly decreased. Further, we show that M1 potentiation with the positive allosteric modulator (PAM) VU0453595 (VU595) rescued social preference, spatial memory, and associative memory deficits, as well as decreased apneas in Mecp2+/- mice. VU595’s efficacy on apneas in Mecp2+/- mice was mediated by the facilitation of the transition from inspiration to expiration. Molecular analysis correlated rescue with normalized global gene expression patterns in the brainstem and hippocampus, as well as increased Gsk3β inhibition and NMDA receptor trafficking. Together, these data suggest that M1 PAMs could represent a new class of RTT therapeutics.
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- 2022
12. mGlu1-mediated restoration of prefrontal cortex inhibitory signaling reverses social and cognitive deficits in an NMDA hypofunction model in mice
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Deborah J. Luessen, Isabel M. Gallinger, Anthony S. Ferranti, Daniel J. Foster, Bruce J. Melancon, Craig W. Lindsley, Colleen M. Niswender, and Jeffrey Conn
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Pharmacology ,Psychiatry and Mental health - Published
- 2022
13. Persistent challenges in the development of an mGlu
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Jacob J, Kalbfleisch, Alice L, Rodriguez, Xia, Lei, Kelly, Weiss, Annie L, Blobaum, Olivier, Boutaud, Colleen M, Niswender, and Craig W, Lindsley
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Herein, we report on the further chemical optimization of the first reported mGlu
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- 2022
14. Activating mGlu3 Metabotropic Glutamate Receptors Rescues Schizophrenia-like Cognitive Deficits Through Metaplastic Adaptations Within the Hippocampus
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Rocco G. Gogliotti, Weilun Qian, Ferdinando Nicoletti, Max E. Joffe, P. Jeffrey Conn, Shalini Dogra, Colleen M. Niswender, Branden J. Stansley, Craig W. Lindsley, and Zixiu Xiang
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0301 basic medicine ,Receptor expression ,Hippocampus ,Long-term potentiation ,Cognition ,mGlu ,3 ,5 ,Schizophrenia ,Synaptic plasticity ,Biology ,Associative learning ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Metabotropic glutamate receptor ,Metaplasticity ,Fear conditioning ,Neuroscience ,030217 neurology & neurosurgery ,Biological Psychiatry - Abstract
Background Polymorphisms in GRM3, the gene encoding the mGlu3 metabotropic glutamate receptor, are associated with impaired cognition and neuropsychiatric disorders such as schizophrenia. Limited availability of selective genetic and molecular tools has hindered progress in developing a clear understanding of the mechanisms through which mGlu3 receptors regulate synaptic plasticity and cognition. Methods We examined associative learning in mice with trace fear conditioning, a hippocampal-dependent learning task disrupted in patients with schizophrenia. Underlying cellular mechanisms were assessed using ex vivo hippocampal slice preparations with selective pharmacological tools and selective genetic deletion of mGlu3 receptor expression in specific neuronal subpopulations. Results mGlu3 receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu3 receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through an mGlu5 receptor–dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu3 or mGlu5 from hippocampal pyramidal cells eliminated effects of mGlu3 activation, revealing a novel mechanism by which mGlu3 and mGlu5 interact to enhance cognitive function. Conclusions These data demonstrate that activation of mGlu3 receptors in hippocampal pyramidal cells enhances hippocampal-dependent cognition in control and impaired mice by inducing a novel form of metaplasticity to regulate circuit function, providing a clear mechanism through which genetic variation in GRM3 can contribute to cognitive deficits. Developing approaches to positively modulate mGlu3 receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases.
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- 2021
15. Discovery of VU6028418: A Highly Selective and Orally Bioavailable M4 Muscarinic Acetylcholine Receptor Antagonist
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Sichen Chang, Jonathan W. Dickerson, Baker Logan A, Thomas M. Bridges, Craig W. Lindsley, Darren W. Engers, Aidong Qi, Jerri M. Rook, Aaron M. Bender, P. Jeffrey Conn, Katrina A. Bollinger, Colleen M. Niswender, Changho Han, Alice L. Rodriguez, Trever R Carter, Li Peng, Julie L. Engers, Jordan C. O’Neill, Matthew Spock, and Katherine J. Watson
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Dystonia ,Movement disorders ,Chemistry ,Organic Chemistry ,Antagonist ,Pharmacology ,medicine.disease ,Highly selective ,Biochemistry ,In vitro ,Bioavailability ,In vivo ,Drug Discovery ,Muscarinic acetylcholine receptor ,medicine ,medicine.symptom - Abstract
[Image: see text] Herein, we report the SAR leading to the discovery of VU6028418, a potent M(4) mAChR antagonist with high subtype-selectivity and attractive DMPK properties in vitro and in vivo across multiple species. VU6028418 was subsequently evaluated as a preclinical candidate for the treatment of dystonia and other movement disorders. During the characterization of VU6028418, a novel use of deuterium incorporation as a means to modulate CYP inhibition was also discovered.
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- 2021
16. Discovery of the First Selective M4 Muscarinic Acetylcholine Receptor Antagonists with in Vivo Antiparkinsonian and Antidystonic Efficacy
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Jerri M. Rook, Aaron M. Bender, Colleen M. Niswender, Yuping Donsante, P. Jeffrey Conn, Hyekyung P. Cho, Li Peng, Julie L. Engers, Jonathan W. Dickerson, Thomas M. Bridges, Craig W. Lindsley, Ellen J. Hess, Sichen Chang, Aidong Qi, Weimin Peng, Mark S. Moehle, Jordan C. O’Neill, Daniel J. Foster, Alice L. Rodriguez, Zoey Bryant, Katherine J. Watson, and Kaylee J. Stillwell
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Pharmacology ,Dystonia ,Movement disorders ,business.industry ,Central nervous system ,medicine.disease ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Tolerability ,In vivo ,Muscarinic acetylcholine receptor ,Genetic model ,Medicine ,Pharmacology (medical) ,medicine.symptom ,business ,Neurotransmitter - Abstract
Nonselective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson's disease and dystonia. Despite their efficacy in these and other central nervous system disorders, antimuscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the antiparkinsonian and antidystonic efficacy observed with the use of nonselective antimuscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of nonselective antimuscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here, we utilize genetic mAChR knockout animals in combination with nonselective mAChR antagonists to confirm that the M4 receptor activation is required for the locomotor-stimulating and antiparkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have antiparkinsonian and antidystonic efficacy in pharmacological and genetic models of movement disorders.
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- 2021
17. Discovery of 'Molecular Switches' within a Series of mGlu5 Allosteric Ligands Driven by a 'Magic Methyl' Effect Affording Both PAMs and NAMs with In Vivo Activity, Derived from an M1 PAM Chemotype
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Darren W. Engers, Natasha Billard, Colleen M. Niswender, Ashlyn N. Blevins, Olivier Boutaud, Jonathan W. Dickerson, P. Jeffrey Conn, Jerri L. Rook, Craig W. Lindsley, Alice L. Rodriguez, and Lisa Barbaro
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Molecular switch ,Chemotype ,Chemistry ,Stereochemistry ,QH301-705.5 ,Allosteric regulation ,Magic (programming) ,Pharmaceutical Science ,QD415-436 ,Biochemistry ,In vivo ,Drug Discovery ,Biology (General) ,Molecular Biology - Published
- 2021
18. Regulation and functional consequences of mGlu4 RNA editing
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Christopher S. Hofmann, Karen J. Gregory, Colleen M. Niswender, Sheridan J. S. Carrington, and Andrew N. Keller
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RNA editing ,G protein ,Metabotropic glutamate receptor 4 ,ADAR ,Glutamate receptor ,RNA ,Biology ,Heteroreceptor ,Receptor ,Molecular Biology ,Cell biology - Abstract
Metabotropic glutamate receptor 4 (mGlu4) is one of eight mGlu receptors within the Class C G protein-coupled receptor superfamily. mGlu4 is primarily localized to the presynaptic membrane of neurons where it functions as an auto and heteroreceptor controlling synaptic release of neurotransmitter. mGlu4 is implicated in numerous disorders and is a promising drug target; however, more remains to be understood about its regulation and pharmacology. Using high-throughput sequencing, we have validated and quantified an adenosine-to-inosine (A-to-I) RNA editing event that converts glutamine 124 to arginine in mGlu4; additionally, we have identified a rare but novel K129R site. Using an in vitro editing assay, we then validated the pre-mRNA duplex that allows for editing by ADAR enzymes and predicted its conservation across the mammalian species. Structural modeling of the mGlu4 protein predicts the Q124R substitution to occur in the B helix of the receptor that is critical for receptor dimerization and activation. Interestingly, editing of a receptor homodimer does not disrupt G protein activation in response to the endogenous agonist, glutamate. Using an assay designed to specifically measure heterodimer populations at the surface, however, we found that Q124R substitution decreased the propensity of mGlu4 to heterodimerize with mGlu2 and mGlu7. Our study is the first to extensively describe the extent and regulatory factors of RNA editing of mGlu4 mRNA transcripts. In addition, we have proposed a novel functional consequence of this editing event that provides insights regarding its effects in vivo and expands the regulatory capacity for mGlu receptors.
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- 2021
19. Differential activity of mGlu
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Xin, Lin, Nicole M, Fisher, Shalini, Dogra, Rebecca K, Senter, Carson W, Reed, Jacob J, Kalbfleisch, Craig W, Lindsley, Wesley B, Asher, Zixiu, Xiang, Colleen M, Niswender, and Jonathan A, Javitch
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Electrophysiology ,Long-Term Potentiation ,Synapses ,Glutamic Acid ,Animals ,Rodentia ,Saccharomyces cerevisiae ,Receptors, Metabotropic Glutamate ,Hippocampus - Abstract
Glutamate acts at eight metabotropic glutamate (mGlu) receptor subtypes expressed in a partially overlapping fashion in distinct brain circuits. Recent evidence indicates that specific mGlu receptor protomers can heterodimerize and that these heterodimers can exhibit different pharmacology when compared to their homodimeric counterparts. Group III mGlu agonist-induced suppression of evoked excitatory potentials and induction of long-term potentiation at Schaffer collateral-CA1 (SC-CA1) synapses in the rodent hippocampus can be blocked by the selective mGlu
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- 2022
20. Discovery of a potent M
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Douglas L, Orsi, Andrew S, Felts, Alice L, Rodriguez, Paige N, Vinson, Hyekyung P, Cho, Sichen, Chang, Anna L, Blobaum, Colleen M, Niswender, P Jeffrey, Conn, Carrie K, Jones, Craig W, Lindsley, and Changho, Han
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Kinetics ,Pyrrolidines ,Muscarinic Antagonists ,Amides - Abstract
This Letter describes our ongoing effort to improve the clearance of selective M
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- 2022
21. GRM7 gene mutations and consequences for neurodevelopment
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Geanne A. Freitas and Colleen M. Niswender
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Pharmacology ,Behavioral Neuroscience ,Clinical Biochemistry ,Toxicology ,Biochemistry ,Biological Psychiatry - Published
- 2023
22. Frontal cortex genetic ablation of metabotropic glutamate receptor subtype 3 (mGlu3) impairs postsynaptic plasticity and modulates affective behaviors
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Colleen M. Niswender, P. Jeffrey Conn, Nicole M. Fisher, Sheryl Anne D. Vermudez, Chiaki I. Santiago, Shalini Dogra, and Max E. Joffe
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Pharmacology ,Glutamate receptor ,Biology ,030227 psychiatry ,03 medical and health sciences ,Psychiatry and Mental health ,0302 clinical medicine ,Metabotropic receptor ,Postsynaptic potential ,Metabotropic glutamate receptor ,Synaptic plasticity ,Excitatory postsynaptic potential ,Prefrontal cortex ,Receptor ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Clinical and translational studies suggest that prefrontal cortex (PFC) dysregulation is a hallmark feature of several affective disorders. Thus, investigating the mechanisms involved in the regulation of PFC function and synaptic plasticity could aid in developing new medications. In recent years, the mGlu2 and mGlu3 subtypes of metabotropic glutamate (mGlu) receptors have emerged as exciting potential targets for the treatment of affective disorders, as mGlu2/3 antagonists exert antidepressant-like effects across many rodent models. Several recent studies suggest that presynaptic mGlu2 receptors may contribute to these effects by regulating excitatory transmission at synapses from the thalamus to the PFC. Interestingly, we found that mGlu3 receptors also inhibit excitatory drive to the PFC but act by inducing long-term depression (LTD) at amygdala-PFC synapses. It remains unclear, however, whether blockade of presynaptic, postsynaptic, or glial mGlu3 receptors contribute to long-term effects on PFC circuit function and antidepressant-like effects of mGlu2/3 antagonists. To address these outstanding questions, we leveraged transgenic Grm3fl/fl mice and viral-mediated gene transfer to genetically ablate mGlu3 receptors from pyramidal cells in the frontal cortex of adult mice of all sexes. Consistent with a role for mGlu3 in PFC pyramidal cells, mGlu3-dependent amygdala-cortical LTD was eliminated following mGlu3 receptor knockdown. Furthermore, knockdown mice displayed a modest, task-specific anxiolytic phenotype and decreased passive coping behaviors. These studies reveal that postsynaptic mGlu3 receptors are critical for mGlu3-dependent LTD and provide convergent genetic evidence suggesting that modulating cortical mGlu3 receptors may provide a promising new approach for the treatment of mood disorders.
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- 2021
23. Impact of MeCP2 Overexpression on Myelination Defects Found in Pitt‐Hopkins Syndrome Model Mice
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Geanne A. Freitas, Sheryl A. D. Vermudez, Rocco G. Gogliotti, and Colleen M. Niswender
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
24. Development of
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Aaron T, Garrison, Douglas L, Orsi, Rory A, Capstick, David, Whomble, Jinming, Li, Trever R, Carter, Andrew S, Felts, Paige N, Vinson, Alice L, Rodriguez, Allie, Han, Krishma, Hajari, Hyekyung P, Cho, Laura B, Teal, Madeline G, Ragland, Masoud, Ghamari-Langroudi, Michael, Bubser, Sichen, Chang, Nathalie C, Schnetz-Boutaud, Olivier, Boutaud, Anna L, Blobaum, Daniel J, Foster, Colleen M, Niswender, P Jeffrey, Conn, Craig W, Lindsley, Carrie K, Jones, and Changho, Han
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Male ,Rats, Sprague-Dawley ,Receptor, Muscarinic M5 ,Dopaminergic Neurons ,Receptor, Muscarinic M1 ,Animals ,Opioid-Related Disorders ,Receptors, Muscarinic ,Rats - Abstract
The muscarinic acetylcholine receptor (mAChR) subtype 5 (M
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- 2022
25. Persistent challenges in the development of an mGlu7 PAM in vivo tool compound: The discovery of VU6046980
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Jacob J. Kalbfleisch, Alice L. Rodriguez, Xia Lei, Kelly Weiss, Annie L. Blobaum, Olivier Boutaud, Colleen M. Niswender, and Craig W. Lindsley
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Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry - Published
- 2023
26. Development and profiling of mGlu
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Carson W, Reed, Alice L, Rodriguez, Jacob J, Kalbfleisch, Mabel, Seto, Matthew T, Jenkins, Anna L, Blobaum, Sichen, Chang, Craig W, Lindsley, and Colleen M, Niswender
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Allosteric Regulation ,Ligands - Abstract
We describe here a series of metabotropic glutamate receptor 7 (mGlu
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- 2022
27. mGlu
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Deborah J, Luessen, Isabel M, Gallinger, Anthony S, Ferranti, Daniel J, Foster, Bruce J, Melancon, Craig W, Lindsley, Colleen M, Niswender, and Jeffrey, Conn
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Mice ,Cognition ,N-Methylaspartate ,Animals ,Glutamic Acid ,Prefrontal Cortex ,Dizocilpine Maleate ,Receptors, Metabotropic Glutamate - Abstract
Extensive evidence supports the hypothesis that deficits in inhibitory GABA transmission in the prefrontal cortex (PFC) may drive pathophysiological changes underlying symptoms of schizophrenia that are not currently treated by available medications, including cognitive and social impairments. Recently, the mGlu
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- 2022
28. Development and Profiling of mGlu 7 NAMs with a Range of in vitro Efficacies
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Carson W. Reed, Alice L. Rodriguez, Jacob J. Kalbfleisch, Mabel Seto, Matthew T. Jenkins, Anna L. Blobaum, Sichen Chang, Craig W. Lindsley, and Colleen M. Niswender
- Published
- 2022
29. Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu7 Positive Allosteric Modulator Tool Compound
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Carson W. Reed, Jordan P Washecheck, Alice L. Rodriguez, P. Jeffrey Conn, Anna L. Blobaum, Colleen M. Niswender, Ashton Hunter, Craig W. Lindsley, Madison J Wong, and Jacob J. Kalbfleisch
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Allosteric modulator ,010405 organic chemistry ,Organic Chemistry ,Rett syndrome ,Pharmacology ,medicine.disease ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Cns penetration ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,Metabotropic glutamate receptor ,Drug Discovery ,medicine ,Penetrant (biochemical) - Abstract
Herein, we report the discovery of the first selective and CNS penetrant mGlu7 PAM (VU6027459) derived from a "molecular switch" within a selective mGlu7 NAM chemotype. VU6027459 displayed CNS penetration in both mice (Kp = 2.74) and rats (Kp= 4.78), it was orally bioavailable in rats (%F = 69.5), and undesired activity at DAT was ablated.
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- 2020
30. In Vitro to in Vivo Translation of Allosteric Modulator Concentration-Effect Relationships: Implications for Drug Discovery
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Shaun R. Stauffer, Rocco G. Gogliotti, P. Jeffrey Conn, Craig W. Lindsley, Carrie K. Jones, Thomas M. Bridges, Colleen M. Niswender, Karen J. Gregory, and Meredith J. Noetzel
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Pharmacology ,Allosteric modulator ,Drug discovery ,Metabotropic glutamate receptor 5 ,Chemistry ,Allosteric regulation ,Cooperativity ,Mechanism of action ,Drug development ,In vivo ,parasitic diseases ,medicine ,Biophysics ,Pharmacology (medical) ,medicine.symptom - Abstract
[Image: see text] Allosteric modulation of GPCRs represents an increasingly explored approach in drug development. Due to complex pharmacology, however, the relationship(s) between modulator properties determined in vitro with in vivo concentration-effect phenomena is frequently unclear. We investigated key pharmacological properties of a set of metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) and their relevance to in vivo concentration–response relationships. These studies identified a significant relationship between in vitro PAM cooperativity (αβ), as well as the maximal response obtained from a simple in vitro PAM concentration–response experiment, with in vivo efficacy for reversal of amphetamine-induced hyperlocomotion. This correlation did not exist with PAM potency or affinity. Data across PAMs were then converged to calculate an in vivo concentration of glutamate putatively relevant to the mGlu(5) PAM mechanism of action. This work demonstrates the ability to merge in vitro pharmacology profiles with relevant behavioral outcomes and also provides a novel method to estimate neurotransmitter concentrations in vivo.
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- 2019
31. Challenges in the Discovery and Optimization of mGlu2/4 Heterodimer Positive Allosteric Modulators
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Charles David Weaver, Emily Days, Craig W. Lindsley, Alice L. Rodriguez, Paige N. Vinson, Colleen M. Niswender, Anna L. Blobaum, Matthew T. Loch, Caroline Anne Cuoco, P.J. Conn, Krystian A. Kozek, and Mark G. Fulton
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medicine.drug_class ,Stereochemistry ,Allosteric regulation ,Pharmaceutical Science ,Carboxamide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Amide ,Drug Discovery ,medicine ,Structure–activity relationship ,metabotropic glutamate receptor ,Receptor ,Xanthine oxidase inhibitor ,Heterodimer ,striatopallidal synapses ,030304 developmental biology ,Letters in Drug Design & Discovery ,0303 health sciences ,mGlu2/4 ,Chemistry ,structure-activity relationship ,Metabotropic glutamate receptor ,positive allosteric modulator ,Molecular Medicine ,Febuxostat ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background: This article describes the challenges in the discovery and optimization of mGlu2/4 heterodimer Positive Allosteric Modulators (PAMs). Methods: Initial forays based on VU0155041, a PAM of both the mGlu4 homodimer and the mGlu2/4 heterodimer, led to flat, intractable SAR that precluded advancement. Screening of a collection of 1,152 FDA approved drugs led to the discovery that febuxostat, an approved xanthine oxidase inhibitor, was a moderately potent PAM of the mGlu2/4 heterodimer (EC50 = 3.4 µM), but was peripherally restricted (rat Kp = 0.03). Optimization of this hit led to PAMs with improved potency (EC50s 2, an ~100-fold increase). Results: However, these new amide analogs of febuxostat proved to be either GIRK1/2 and GIRK1/4 activators (primary carboxamide congeners) or mGlu2 PAMs (secondary and tertiary amides) and not selective mGlu2/4 heterodimer PAMs. Conclusion: These results required the team to develop a new screening cascade paradigm, and exemplified the challenges in developing allosteric ligands for heterodimeric receptors.
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- 2019
32. Exploration of group II metabotropic glutamate receptor modulation in mouse models of Rett syndrome and MECP2 Duplication syndrome
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Sheryl Anne D. Vermudez, Aditi Buch, Kelly Weiss, Rocco G. Gogliotti, and Colleen M. Niswender
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Pharmacology ,Mice, Inbred C57BL ,Mice, Knockout ,Cellular and Molecular Neuroscience ,Disease Models, Animal ,Mice ,Methyl-CpG-Binding Protein 2 ,Mental Retardation, X-Linked ,Rett Syndrome ,Animals ,Humans ,Receptors, Metabotropic Glutamate ,Article - Abstract
Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) have opposing molecular origins in relation to expression and function of the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2). Several clinical and preclinical phenotypes, however, are shared between these disorders. Modulation of MeCP2 levels has recently emerged as a potential treatment option for both of these diseases. However, toxicity concerns remain with these approaches. Here, we focus on pharmacologically modulating the group II metabotropic glutamate receptors (mGlu), mGlu(2) and mGlu(3), which are two downstream targets of MeCP2 that are bidirectionally affected in expression in RTT patients and mice (Mecp2(Null/+)) versus an MDS mouse model (MECP2(Tg1/o)). Mecp2(Null/+) and MECP2(Tg1/o) animals also exhibit contrasting phenotypes in trace fear acquisition, a form of temporal associative learning and memory, with trace fear deficiency observed in Mecp2(Null/+) mice and abnormally enhanced trace fear acquisition in MECP2(Tg1/o) animals. In Mecp2(Null/+) mice, treatment with the mGlu(2/3) agonist LY379268 reverses the deficit in trace fear acquisition, and mGlu(2/3) antagonism with LY341495 normalizes the abnormal trace fear learning and memory phenotype in MECP2(Tg1/o) mice. Altogether, these data highlight the role of group II mGlu receptors in RTT and MDS and demonstrate that both mGlu(2) and mGlu(3) may be potential therapeutic targets for these disorders.
- Published
- 2021
33. Discovery of a potent M5 antagonist with improved clearance profile. Part 2: Pyrrolidine amide-based antagonists
- Author
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Douglas L. Orsi, Andrew S. Felts, Alice L. Rodriguez, Paige N. Vinson, Hyekyung P. Cho, Sichen Chang, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Carrie K. Jones, Craig W. Lindsley, and Changho Han
- Subjects
Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry - Published
- 2022
34. Discovery of a potent M5 antagonist with improved clearance profile. Part 1: Piperidine amide-based antagonists
- Author
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Rory A. Capstick, David Whomble, Douglas L. Orsi, Andrew S. Felts, Alice L. Rodriguez, Paige N. Vinson, Sichen Chang, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Carrie K. Jones, Craig W. Lindsley, and Changho Han
- Subjects
Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry - Published
- 2022
35. Development and profiling of mGlu7 NAMs with a range of saturable inhibition of agonist responses in vitro
- Author
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Carson W. Reed, Alice L. Rodriguez, Jacob J. Kalbfleisch, Mabel Seto, Matthew T. Jenkins, Anna L. Blobaum, Sichen Chang, Craig W. Lindsley, and Colleen M. Niswender
- Subjects
Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry - Published
- 2022
36. Metabotropic glutamate receptors in GtoPdb v.2021.3
- Author
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Michihiro Tateyama, Shigetada Nakanishi, James A. Monn, Ryuichi Shigemoto, Robert M. Duvoisin, Hans Bräuner-Osborne, Colleen M. Niswender, P. Jeffrey Conn, Francine Acher, Darryle D. Schoepp, Yoshihiro Kubo, Philippe Rondard, David R. Hampson, Cyril Goudet, Peter J. Flor, Karen J. Gregory, Michael P. Johnson, Francesco Ferraguti, Jean-Philippe Pin, Ferdinando Nicoletti, and Giuseppe Battaglia
- Subjects
Metabotropic receptor ,Chemistry ,Metabotropic glutamate receptor ,Protein subunit ,Biophysics ,medicine ,Ionotropic glutamate receptor ,Kainate receptor ,Cyclothiazide ,AMPA receptor ,Receptor ,medicine.drug - Abstract
The ionotropic glutamate receptors comprise members of the NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) and kainate receptor classes, named originally according to their preferred, synthetic, agonist [35, 92, 155]. Receptor heterogeneity within each class arises from the homo-oligomeric, or hetero-oligomeric, assembly of distinct subunits into cation-selective tetramers. Each subunit of the tetrameric complex comprises an extracellular amino terminal domain (ATD), an extracellular ligand binding domain (LBD), 3 TM domains (M1, M3 and M4), a channel lining re-entrant 'p-loop' (M2) located between M1 and M3 and an intracellular carboxy- terminal domain (CTD) [99, 68, 107, 155, 82]. The X-ray structure of a homomeric ionotropic glutamate receptor (GluA2- see below) has recently been solved at 3.6A resolution [143] and although providing the most complete structural information current available may not representative of the subunit arrangement of, for example, the heteromeric NMDA receptors [71]. It is beyond the scope of this supplement to discuss the pharmacology of individual ionotropic glutamate receptor isoforms in detail; such information can be gleaned from [35, 66, 31, 77, 42, 114, 24, 65, 155, 112, 113, 162]. Agents that discriminate between subunit isoforms are, where appropriate, noted in the tables and additional compounds that distinguish between receptor isoforms are indicated in the text below.The classification of glutamate receptor subunits has been re-addressed by NC-IUPHAR [28]. The scheme developed recommends a nomenclature for ionotropic glutamate receptor subunits that is adopted here.NMDA receptorsNMDA receptors assemble as obligate heteromers that may be drawn from GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B subunits. Alternative splicing can generate eight isoforms of GluN1 with differing pharmacological properties. Various splice variants of GluN2B, 2C, 2D and GluN3A have also been reported. Activation of NMDA receptors containing GluN1 and GluN2 subunits requires the binding of two agonists, glutamate to the S1 and S2 regions of the GluN2 subunit and glycine to S1 and S2 regions of the GluN1 subunit [41, 25]. The minimal requirement for efficient functional expression of NMDA receptors in vitro is a di-heteromeric assembly of GluN1 and at least one GluN2 subunit variant, as a dimer of heterodimers arrangement in the extracellular domain [48, 99, 71]. However, more complex tri-heteromeric assemblies, incorporating multiple subtypes of GluN2 subunit, or GluN3 subunits, can be generated in vitro and occur in vivo. The NMDA receptor channel commonly has a high relative permeability to Ca2+ and is blocked, in a voltage-dependent manner, by Mg2+ such that at resting potentials the response is substantially inhibited.AMPA and Kainate receptorsAMPA receptors assemble as homomers, or heteromers, that may be drawn from GluA1, GluA2, GluA3 and GluA4 subunits. Transmembrane AMPA receptor regulatory proteins (TARPs) of class I (i.e. γ2, γ3, γ4 and γ8) act, with variable stoichiometry, as auxiliary subunits to AMPA receptors and influence their trafficking, single channel conductance gating and pharmacology (reviewed in [43, 103, 153, 64]). Functional kainate receptors can be expressed as homomers of GluK1, GluK2 or GluK3 subunits. GluK1-3 subunits are also capable of assembling into heterotetramers (e.g. GluK1/K2; [87, 119, 118]). Two additional kainate receptor subunits, GluK4 and GluK5, when expressed individually, form high affinity binding sites for kainate, but lack function, but can form heteromers when expressed with GluK1-3 subunits (e.g. GluK2/K5; reviewed in [119, 65, 118]). Kainate receptors may also exhibit 'metabotropic' functions [87, 131]. As found for AMPA receptors, kainate receptors are modulated by auxiliary subunits (Neto proteins, [118, 88]). An important function difference between AMPA and kainate receptors is that the latter require extracellular Na+ and Cl- for their activation [11, 120]. RNA encoding the GluA2 subunit undergoes extensive RNA editing in which the codon encoding a p-loop glutamine residue (Q) is converted to one encoding arginine (R). This Q/R site strongly influences the biophysical properties of the receptor. Recombinant AMPA receptors lacking RNA edited GluA2 subunits are: (1) permeable to Ca2+; (2) blocked by intracellular polyamines at depolarized potentials causing inward rectification (the latter being reduced by TARPs); (3) blocked by extracellular argiotoxin and joro spider toxins and (4) demonstrate higher channel conductances than receptors containing the edited form of GluA2 [139, 63]. GluK1 and GluK2, but not other kainate receptor subunits, are similarly edited and broadly similar functional characteristics apply to kainate receptors lacking either an RNA edited GluK1, or GluK2, subunit [87, 118]. Native AMPA and kainate receptors displaying differential channel conductances, Ca2+ permeabilites and sensitivity to block by intracellular polyamines have been identified [30, 63, 91]. GluA1-4 can exist as two variants generated by alternative splicing (termed ‘flip’ and ‘flop’) that differ in their desensitization kinetics and their desensitization in the presence of cyclothiazide which stabilises the nondesensitized state. TARPs also stabilise the non-desensitized conformation of AMPA receptors and facilitate the action of cyclothiazide [103]. Splice variants of GluK1-3 also exist which affects their trafficking [87, 118].
- Published
- 2021
37. Synthesis and characterization of chiral 6-azaspiro[2.5]octanes as potent and selective antagonists of the M
- Author
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Aaron M, Bender, Trever R, Carter, Matthew, Spock, Alice L, Rodriguez, Jonathan W, Dickerson, Jerri M, Rook, Sichen, Chang, Aidong, Qi, Christopher C, Presley, Darren W, Engers, Joel M, Harp, Thomas M, Bridges, Colleen M, Niswender, P Jeffrey, Conn, and Craig W, Lindsley
- Subjects
Structure-Activity Relationship ,Dose-Response Relationship, Drug ,Molecular Structure ,Receptor, Muscarinic M4 ,Humans ,Muscarinic Antagonists - Abstract
In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR
- Published
- 2021
38. Discovery of structurally distinct tricyclic M
- Author
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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, and Kayla J, Temple
- Subjects
Structure-Activity Relationship ,Pyrimidines ,Dose-Response Relationship, Drug ,Molecular Structure ,Receptor, Muscarinic M4 ,Drug Discovery ,Humans ,Article - Abstract
This Letter details our efforts to develop novel tricyclic M(4) PAM scaffolds with improved pharmacological properties. This endeavor involved a “tie-back” strategy to replace the 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3’,2’:4,5]thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3-b:5,4-c’]dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M(4) receptor.
- Published
- 2021
39. Profiling beneficial and potential adverse effects of <scp>MeCP2</scp> overexpression in a hypomorphic Rett syndrome mouse model
- Author
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Colleen M. Niswender, P. Jeffrey Conn, Bright Arthur, Hemangi Rajpal, Yuta Moxley, Rocco G. Gogliotti, Sheryl Anne D. Vermudez, Clarissa Morales, and Aditi B. Buch
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Mutation ,Transgene ,MECP2 duplication syndrome ,Rett syndrome ,Disease ,Biology ,medicine.disease ,Bioinformatics ,medicine.disease_cause ,Phenotype ,nervous system diseases ,MECP2 ,03 medical and health sciences ,Behavioral Neuroscience ,030104 developmental biology ,0302 clinical medicine ,Neurodevelopmental disorder ,Neurology ,mental disorders ,Genetics ,medicine ,030217 neurology & neurosurgery - Abstract
De novo loss-of-function mutations in methyl-CpG-binding protein 2 (MeCP2) lead to the neurodevelopmental disorder Rett syndrome (RTT). Despite promising results from strategies aimed at increasing MeCP2 levels, additional studies exploring how hypomorphic MeCP2 mutations impact the therapeutic window are needed. Here, we investigated the consequences of genetically introducing a wild-type MECP2 transgene in the Mecp2 R133C mouse model of RTT. The MECP2 transgene reversed the majority of RTT-like phenotypes exhibited by male and female Mecp2 R133C mice. However, three core symptom domains were adversely affected in female Mecp2R133C/+ animals; these phenotypes resemble those observed in disease contexts of excess MeCP2. Parallel control experiments in Mecp2Null/+ mice linked these adverse effects to the hypomorphic R133C mutation. Collectively, these data provide evidence regarding the safety and efficacy of genetically overexpressing functional MeCP2 in Mecp2 R133C mice and suggest that personalized approaches may warrant consideration for the clinical assessment of MeCP2-targeted therapies.
- Published
- 2021
40. Input-specific regulation of glutamatergic synaptic transmission in the medial prefrontal cortex by mGlu
- Author
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Zixiu, Xiang, Xiaohui, Lv, Xin, Lin, Daniel E, O'Brien, Molly K, Altman, Craig W, Lindsley, Jonathan A, Javitch, Colleen M, Niswender, and P Jeffrey, Conn
- Subjects
nervous system ,musculoskeletal, neural, and ocular physiology ,Synapses ,Prefrontal Cortex ,Synaptic Transmission ,Article - Abstract
Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that regulate various aspects of central nervous system processing in normal physiology and in disease. They are thought to function as disulfide-linked homodimers, but studies have suggested that mGluRs can form functional heterodimers in cell lines. Using selective allosteric ligands, ex vivo brain slice electrophysiology, and optogenetic approaches, we found that two mGluR subtypes—mGluR2 and mGluR4 (or mGlu(2) and mGlu(4))—exist as functional heterodimers that regulate excitatory transmission in a synapse-specific manner within the rodent medial prefrontal cortex (mPFC). Activation of mGlu(2)/mGlu(4) heterodimers inhibited glutamatergic signaling at thalamo-mPFC synapses but not at hippocampus-mPFC or amygdala-mPFC synapses. These findings raise the possibility that selectively targeting these heterodimers could be a therapeutic strategy for some neurologic and neuropsychiatric disorders involving specific brain circuits.
- Published
- 2021
41. Input-specific regulation of glutamatergic synaptic transmission in the medial prefrontal cortex by mGlu 2 /mGlu 4 receptor heterodimers
- Author
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Colleen M. Niswender, Daniel E. O’Brien, Xiaohui Lv, Molly K. Altman, Zixiu Xiang, Craig W. Lindsley, Xin Lin, Jonathan A. Javitch, and P. Jeffrey Conn
- Subjects
0303 health sciences ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Cell Biology ,Optogenetics ,Neurotransmission ,Biochemistry ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Slice preparation ,nervous system ,Metabotropic glutamate receptor ,Excitatory postsynaptic potential ,Receptor ,Prefrontal cortex ,Molecular Biology ,Neuroscience ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that regulate various aspects of central nervous system processing in normal physiology and in disease. They are thought to function as disulfide-linked homodimers, but studies have suggested that mGluRs can form functional heterodimers in cell lines. Using selective allosteric ligands, ex vivo brain slice electrophysiology, and optogenetic approaches, we found that two mGluR subtypes-mGluR2 and mGluR4 (or mGlu2 and mGlu4)-exist as functional heterodimers that regulate excitatory transmission in a synapse-specific manner within the rodent medial prefrontal cortex (mPFC). Activation of mGlu2/mGlu4 heterodimers inhibited glutamatergic signaling at thalamo-mPFC synapses but not at hippocampus-mPFC or amygdala-mPFC synapses. These findings raise the possibility that selectively targeting these heterodimers could be a therapeutic strategy for some neurologic and neuropsychiatric disorders involving specific brain circuits.
- Published
- 2021
42. Further exploration of an N-aryl phenoxyethoxy pyridinone-based series of mGlu3 NAMs: Challenging SAR, enantiospecific activity and in vivo efficacy
- Author
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Kristen Gilliland, Anna L. Blobaum, Samantha E. Yohn, P. Jeffrey Conn, Craig W. Lindsley, Michael L. Schulte, Alice L. Rodriguez, Colleen M. Niswender, Mathew T. Loch, and Yousuke Yamada
- Subjects
Tail Suspension ,010405 organic chemistry ,Stereochemistry ,Aryl ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Selective inhibition ,01 natural sciences ,Biochemistry ,Zero maze ,0104 chemical sciences ,Marble burying ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,In vivo ,Multidimensional optimization ,Drug Discovery ,Molecular Medicine ,G protein-coupled inwardly-rectifying potassium channel ,Molecular Biology - Abstract
This letter describes the further optimization of a series of mGlu3 NAMs based on an N-aryl phenoxyethoxy pyridinone core. A multidimensional optimization campaign, with focused matrix libraries, quickly established challenging SAR, enantiospecific activity, differences in assay read-outs (Ca2+ flux via a promiscuous G protein (Gα15) versus native coupling to GIRK channels), identified both full and partial mGlu3 NAMs and a new in vivo tool compound, VU6017587. This mGlu3 NAM showed efficacy in tail suspension, elevated zero maze and marble burying, suggesting selective inhibition of mGlu3 affords anxiolytic-like and antidepressant-like phenotypes in mice.
- Published
- 2019
43. SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M4 PAMs
- Author
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Changho Han, J. Scott Daniels, Alice L. Rodriguez, Colleen M. Niswender, Alison R. Gregro, P. Jeffrey Conn, Michael R. Wood, Craig W. Lindsley, Katrina A. Bollinger, Michael W. Wood, Mark E. Duggan, Sichen Chang, Darren W. Engers, Atin Lamsal, Ryan D. Morrison, Andrew S. Felts, Trevor C. Chopko, Nicholas J. Brandon, Nathalie Schnetz-Boutaud, Vincent B. Luscombe, Hyekyung P. Cho, Mike Poslusney, Carrie K. Jones, Donald F. Stec, Thomas M. Bridges, Michael Bubser, and Bruce J. Melancon
- Subjects
chemistry.chemical_classification ,010405 organic chemistry ,Stereochemistry ,Metabolite ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Metabolism ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Cns penetration ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,In vivo ,Drug Discovery ,Molecular Medicine ,Penetrant (biochemical) ,Molecular Biology ,Aldehyde oxidase ,Tricyclic - Abstract
This letter describes progress towards an M4 PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M4 PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.
- Published
- 2019
44. Evaluation of Synthetic Cytochrome P450-Mimetic Metalloporphyrins To Facilitate 'Biomimetic' Biotransformation of a Series of mGlu5 Allosteric Ligands
- Author
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Colleen M. Niswender, Christopher C Presley, P. Jeffrey Conn, Vincent B. Luscombe, Alice L. Rodriguez, Charles K. Perry, Craig W. Lindsley, Matthew J. Mulder, and Elizabeth S. Childress
- Subjects
Molecular switch ,Cytochrome ,biology ,Ligand ,General Chemical Engineering ,Metabolite ,Allosteric regulation ,General Chemistry ,Combinatorial chemistry ,lcsh:Chemistry ,chemistry.chemical_compound ,lcsh:QD1-999 ,chemistry ,Biotransformation ,In vivo ,biology.protein ,G protein-coupled receptor - Abstract
Allosteric ligands within a given chemotype can have the propensity to display a wide range of pharmacology, as well as unexpected changes in GPCR subtype selectivity, typically mediated by single-atom modifications to the ligand. Due to the unexpected nature of these "molecular switches", chemotypes with this property are typically abandoned in lead optimization. Recently, we have found that in vivo oxidative metabolism by CYP450s can also engender molecular switches within allosteric ligands, changing the mode of pharmacology and leading to unwanted toxicity. We required a higher-throughput approach to assess in vivo metabolic molecular switches, and we turned to a "synthetic liver", a 96 well kit of biomimetic catalysts (e.g., metalloporphyrins) to rapidly survey a broad panel of synthetic CYP450s' ability to oxidize/"metabolize" an mGlu5 PAM (VU0403602) known to undergo an in vivo CYP450-mediated molecular switch. While the synthetic CYP450s did generate a number of oxidative "metabolites" at known "hot spots", several of which proved to be pure mGlu5 PAMs comparable in potency to the parent, the known CYP450-mediated in vivo ago-PAM metabolite, namely, VU0453103, was not formed. Thus, this technology platform has potential to identify hot spots for oxidative metabolism and produce active metabolites of small-molecule ligands in a high-throughput, scalable manner.
- Published
- 2019
45. VU6005806/AZN-00016130, an advanced M4 positive allosteric modulator (PAM) profiled as a potential preclinical development candidate
- Author
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Alice L. Rodriguez, P. Jeffrey Conn, Allison R. Gregro, Michael Bubser, Mark E. Dugan, Colleen M. Niswender, Leah C. Konkol, Michael W. Wood, Darren W. Engers, Craig W. Lindsley, Jeanette L. Bertron, Bruce J. Melancon, Sean R. Bollinger, Thomas M. Bridges, Samantha E. Yohn, Vincent B. Luscombe, Andrew S. Felts, Michael R. Wood, Carrie K. Jones, Nicholas J. Brandon, and Katrina A. Bollinger
- Subjects
Allosteric modulator ,010405 organic chemistry ,medicine.drug_class ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Carboxamide ,Computational biology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Pyridazine ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,In vivo ,Drug Discovery ,medicine ,Molecular Medicine ,Moiety ,Pharmaceutical sciences ,Molecular Biology - Abstract
This letter describes progress towards an M4 PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3-c]pyridazine core has been a consistent feature of key M4 PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the β-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe.
- Published
- 2019
46. mGlu5 Positive Allosteric Modulators Facilitate Long-Term Potentiation via Disinhibition Mediated by mGlu5-Endocannabinoid Signaling
- Author
-
Colleen M. Niswender, P. Jeffrey Conn, Branden J. Stansley, Ayan Ghoshal, Rocco G. Gogliotti, Zixiu Xiang, Craig W. Lindsley, Xiaohui Lv, and James Maksymetz
- Subjects
Pharmacology ,AM251 ,0303 health sciences ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Long-term potentiation ,Inhibitory postsynaptic potential ,Endocannabinoid system ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Metabotropic receptor ,nervous system ,Schaffer collateral ,Cannabinoid receptor type 1 ,medicine ,NMDA receptor ,Pharmacology (medical) ,Neuroscience ,psychological phenomena and processes ,030217 neurology & neurosurgery ,030304 developmental biology ,medicine.drug - Abstract
[Image: see text] Metabotropic glutamate (mGlu) receptor type 5 (mGlu(5)) positive allosteric modulators (PAMs) enhance hippocampal long-term potentiation (LTP) and have cognition-enhancing effects in animal models. These effects were initially thought to be mediated by potentiation of mGlu(5) modulation of N-methyl-d-aspartate receptor (NMDAR) currents. However, a biased mGlu(5) PAM that potentiates Gα(q)-dependent mGlu(5) signaling, but not mGlu(5) modulation of NMDAR currents, retains cognition-enhancing effects in animal models, suggesting that potentiation of NMDAR currents is not required for these in vivo effects of mGlu(5) PAMs. However, it is not clear whether the potentiation of NMDAR currents is critical for the ability of mGlu(5) PAMs to enhance hippocampal LTP. We now report the characterization of effects of two structurally distinct mGlu(5) PAMs, VU-29 and VU0092273, on NMDAR currents and hippocampal LTP. As with other mGlu(5) PAMs that do not display observable bias for potentiation of NMDAR currents, VU0092273 enhanced both mGlu(5) modulation of NMDAR currents and induction of LTP at the hippocampal Schaffer collateral (SC)-CA1 synapse. In contrast, VU-29 did not potentiate mGlu(5) modulation of NMDAR currents but induced robust potentiation of hippocampal LTP. Interestingly, both VU-29 and VU0092273 suppressed evoked inhibitory postsynaptic currents (eIPSCs) in CA1 pyramidal cells, and this effect was blocked by the cannabinoid receptor type 1 (CB1) antagonist AM251. Furthermore, AM251 blocked the ability of both mGlu(5) PAMs to enhance LTP. Finally, both PAMs failed to enhance LTP in mice with the restricted genetic deletion of mGlu(5) in CA1 pyramidal cells. Taken together with previous findings, these results suggest that enhancement of LTP by mGlu(5) PAMs does not depend on mGlu(5) modulation of NMDAR currents but is mediated by a previously established mechanism in which mGlu(5) in CA1 pyramidal cells induces endocannabinoid release and CB1-dependent disinhibition.
- Published
- 2019
47. Surveying heterocycles as amide bioisosteres within a series of mGlu7 NAMs: Discovery of VU6019278
- Author
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Carson W. Reed, Matthew T. Jenkins, Colleen M. Niswender, Alice L. Rodriguez, P. Jeffrey Conn, Darren W. Engers, Marc C. Quitlag, Craig W. Lindsley, Jordan P Washecheck, and Anna L. Blobaum
- Subjects
010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Hepatic clearance ,Plasma protein binding ,Ring (chemistry) ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,Metabotropic glutamate receptor ,Amide ,Drug Discovery ,Molecular Medicine ,Moiety ,Bioisostere ,Molecular Biology - Abstract
This letter describes a diversity-oriented library approach to rapidly assess diverse heterocycles as bioisosteric replacements for a metabolically labile amide moiety within a series of mGlu7 negative allosteric modulators (NAMs). SAR rapidly honed in on either a 1,2,4- or 1,3,4-oxadizaole ring system as an effective bioisostere for the amide. Further optimization of the southern region of the mGlu7 NAM chemotype led to the discovery of VU6019278, a potent mGlu7 NAM (IC50 = 501 nM, 6.3% L-AP4 Min) with favorable plasma protein binding (rat fu = 0.10), low predicted hepatic clearance (rat CLhep = 27.7 mL/min/kg) and high CNS penetration (rat Kp = 4.9, Kp,uu = 0.65).
- Published
- 2019
48. Novel M4 positive allosteric modulators derived from questioning the role and impact of a presumed intramolecular hydrogen-bonding motif in β-amino carboxamide-harboring ligands
- Author
-
Michael S. Poslusney, Alice L. Rodriguez, P. Jeffrey Conn, Craig W. Lindsley, Colleen M. Niswender, Vincent B. Luscombe, Darren W. Engers, Thomas M. Bridges, Katrina A. Bollinger, Michael R. Wood, Bruce J. Melancon, and James M. Salovich
- Subjects
Bicyclic molecule ,010405 organic chemistry ,Hydrogen bond ,Chemistry ,Stereochemistry ,medicine.drug_class ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Carboxamide ,Pyrazole ,01 natural sciences ,Biochemistry ,First generation ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Intramolecular force ,Drug Discovery ,medicine ,Molecular Medicine ,Moiety ,Molecular Biology - Abstract
This letter describes a focused exercise to explore the role of the β-amino carboxamide moiety found in all of the first generation M4 PAMs and question if the NH2 group served solely to stabilize an intramolecular hydrogen bond (IMHB) and enforce planarity. To address this issue (and to potentially find a substitute for the β-amino carboxamide that engendered P-gp and contributed to solubility liabilities), we removed the NH2, generating des-amino congeners and surveyed other functional groups in the β-position. These modifications led to weak M4 PAMs with poor DMPK properties. Cyclization of the β-amino carboxamide moiety by virtue of a pyrazole ring re-enforced the IMHB, led to potent (and patented) M4 PAMs, many as potent as the classical bicyclic β-amino carboxamide analogs, but with significant CYP1A2 inhibition. Overall, this exercise indicated that the β-amino carboxamide moiety most likely facilitates an IMHB, and is essential for M4 PAM activity within classical bicyclic M4 PAM scaffolds.
- Published
- 2019
49. The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate
- Author
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Corey R. Hopkins, Anna L. Blobaum, Joshua M. Wieting, Ryan Westphal, Rory A. Capstick, Alison R. Gregro, Julie E. Engers, Aspen Chun, P. Jeffrey Conn, Jason M. Guernon, Carrie K. Jones, Alice L. Rodriguez, Darren W. Engers, Joseph D. Panarese, Craig W. Lindsley, Wu Yong Jin, Joanne J. Bronson, John E. Macor, Andrew S. Felts, Kyle A. Emmitte, Colleen M. Niswender, Aaron M. Bender, and Matthew Soars
- Subjects
Allosteric modulator ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Computational biology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Cns penetration ,010404 medicinal & biomolecular chemistry ,Metabotropic glutamate receptor ,Drug Discovery ,Molecular Medicine ,skin and connective tissue diseases ,Molecular Biology - Abstract
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
- Published
- 2019
50. Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5
- Author
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J. Scott Daniels, Christopher J. Brassard, Ryan D. Morrison, Alice L. Rodriguez, Anna L. Blobaum, Kyle A. Emmitte, Andrew S. Felts, P. Jeffrey Conn, Colleen M. Niswender, Carrie K. Jones, Katrina A. Bollinger, and Craig W. Lindsley
- Subjects
Pyrimidine ,Stereochemistry ,Receptor, Metabotropic Glutamate 5 ,Metabolite ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Ligands ,01 natural sciences ,Biochemistry ,Article ,Structure-Activity Relationship ,chemistry.chemical_compound ,Allosteric Regulation ,Drug Discovery ,Animals ,Humans ,Moiety ,Picolinic Acids ,Molecular Biology ,Aldehyde oxidase ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Ligand (biochemistry) ,Rats ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Metabotropic glutamate receptor ,Molecular Medicine ,Pharmacophore - Abstract
This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp3 character, uniform CYP450-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.
- Published
- 2019
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