10 results on '"Days, Emily"'
Search Results
2. DihydrothiazolopyridoneDerivatives as a Novel Familyof Positive Allosteric Modulators of the Metabotropic Glutamate 5(mGlu5) Receptor.
- Author
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Bartolomé-Nebreda, José Manuel, Conde-Ceide, Susana, Delgado, Francisca, Iturrino, Laura, Pastor, Joaquín, Pena, Miguel Ángel, Trabanco, Andrés A., Tresadern, Gary, Wassvik, Carola M., Stauffer, Shaun R., Jadhav, Satyawan, Gogi, Kiran, Vinson, Paige N., Noetzel, Meredith J., Days, Emily, Weaver, C. David, Lindsley, Craig W., Niswender, Colleen M., Jones, Carrie K., and Conn, P. Jeffrey
- Published
- 2013
- Full Text
- View/download PDF
3. Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx.
- Author
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Dadi PK, Vierra NC, Days E, Dickerson MT, Vinson PN, Weaver CD, and Jacobson DA
- Subjects
- Action Potentials drug effects, Animals, Antibodies pharmacology, Dinoprostone analogs & derivatives, Dinoprostone pharmacology, Electric Stimulation, Fluoxetine pharmacology, HEK293 Cells, Humans, Lectins metabolism, Mice, Mice, Inbred C57BL, Mutation genetics, Potassium Channel Blockers pharmacology, Potassium Channels, Tandem Pore Domain genetics, Potassium Channels, Tandem Pore Domain immunology, Protein Synthesis Inhibitors pharmacology, Tetracycline pharmacology, Action Potentials physiology, Calcium metabolism, Ganglia, Spinal cytology, Nociceptors drug effects, Nociceptors metabolism, Potassium Channels, Tandem Pore Domain metabolism
- Abstract
The two-pore-domain potassium (K2P) channel TREK-2 serves to modulate plasma membrane potential in dorsal root ganglia c-fiber nociceptors, which tunes electrical excitability and nociception. Thus, TREK-2 channels are considered a potential therapeutic target for treating pain; however, there are currently no selective pharmacological tools for TREK-2 channels. Here we report the identification of the first TREK-2 selective activators using a high-throughput fluorescence-based thallium (Tl
+ ) flux screen (HTS). An initial pilot screen with a bioactive lipid library identified 11-deoxy prostaglandin F2α as a potent activator of TREK-2 channels (EC50 ≈ 0.294 μM), which was utilized to optimize the TREK-2 Tl+ flux assay (Z' = 0.752). A HTS was then performed with 76 575 structurally diverse small molecules. Many small molecules that selectively activate TREK-2 were discovered. As these molecules were able to activate single TREK-2 channels in excised membrane patches, they are likely direct TREK-2 activators. Furthermore, TREK-2 activators reduced primary dorsal root ganglion (DRG) c-fiber Ca2+ influx. Interestingly, some of the selective TREK-2 activators such as 11-deoxy prostaglandin F2α were found to inhibit the K2P channel TREK-1. Utilizing chimeric channels containing portions of TREK-1 and TREK-2, the region of the TREK channels that allows for either small molecule activation or inhibition was identified. This region lies within the second pore domain containing extracellular loop and is predicted to play an important role in modulating TREK channel activity. Moreover, the selective TREK-2 activators identified in this HTS provide important tools for assessing human TREK-2 channel function and investigating their therapeutic potential for treating chronic pain.- Published
- 2017
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4. Development and validation of a thallium flux-based functional assay for the sodium channel NaV1.7 and its utility for lead discovery and compound profiling.
- Author
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Du Y, Days E, Romaine I, Abney KK, Kaufmann K, Sulikowski G, Stauffer S, Lindsley CW, and Weaver CD
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- Dose-Response Relationship, Drug, HEK293 Cells, Humans, Patch-Clamp Techniques, Sodium Channel Blockers chemistry, Veratridine pharmacology, Drug Discovery methods, High-Throughput Screening Assays methods, NAV1.7 Voltage-Gated Sodium Channel metabolism, Sodium Channel Blockers pharmacology, Thallium metabolism
- Abstract
Ion channels are critical for life, and they are targets of numerous drugs. The sequencing of the human genome has revealed the existence of hundreds of different ion channel subunits capable of forming thousands of ion channels. In the face of this diversity, we only have a few selective small-molecule tools to aid in our understanding of the role specific ion channels in physiology which may in turn help illuminate their therapeutic potential. Although the advent of automated electrophysiology has increased the rate at which we can screen for and characterize ion channel modulators, the technique's high per-measurement cost and moderate throughput compared to other high-throughput screening approaches limit its utility for large-scale high-throughput screening. Therefore, lower cost, more rapid techniques are needed. While ion channel types capable of fluxing calcium are well-served by low cost, very high-throughput fluorescence-based assays, other channel types such as sodium channels remain underserved by present functional assay techniques. In order to address this shortcoming, we have developed a thallium flux-based assay for sodium channels using the NaV1.7 channel as a model target. We show that the assay is able to rapidly and cost-effectively identify NaV1.7 inhibitors thus providing a new method useful for the discovery and profiling of sodium channel modulators.
- Published
- 2015
- Full Text
- View/download PDF
5. Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7.
- Author
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Jalan-Sakrikar N, Field JR, Klar R, Mattmann ME, Gregory KJ, Zamorano R, Engers DW, Bollinger SR, Weaver CD, Days EL, Lewis LM, Utley TJ, Hurtado M, Rigault D, Acher F, Walker AG, Melancon BJ, Wood MR, Lindsley CW, Conn PJ, Xiang Z, Hopkins CR, and Niswender CM
- Subjects
- Acetanilides chemistry, Acetanilides pharmacology, Animals, Benzoates pharmacology, CHO Cells, Calcium metabolism, Cricetulus, Dose-Response Relationship, Drug, Excitatory Postsynaptic Potentials drug effects, G Protein-Coupled Inwardly-Rectifying Potassium Channels genetics, G Protein-Coupled Inwardly-Rectifying Potassium Channels metabolism, Glutamic Acid pharmacology, Glycine analogs & derivatives, Glycine pharmacology, HEK293 Cells, Hippocampus drug effects, Hippocampus metabolism, Humans, In Vitro Techniques, Male, Mice, Inbred C57BL, Picolinic Acids chemistry, Picolinic Acids pharmacology, Propionates pharmacology, Pyrroles chemistry, Pyrroles pharmacology, Rats, Receptors, Metabotropic Glutamate genetics, Structure-Activity Relationship, Thallium metabolism, Transfection, Excitatory Amino Acid Agents chemistry, Excitatory Amino Acid Agents pharmacology, Receptors, Metabotropic Glutamate metabolism
- Abstract
Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses, and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD, and schizophrenia. Here we report two new pan-group III mGlu positive allosteric modulators, VU0155094 and VU0422288, which show differential activity at the various group III mGlus. Additionally, both compounds show probe dependence when assessed in the presence of distinct orthosteric agonists. By pairing studies of these nonselective compounds with a synapse in the hippocampus that expresses only mGlu7, we have validated activity of these compounds in a native tissue setting. These studies provide proof-of-concept evidence that mGlu7 activity can be modulated by positive allosteric modulation, paving the way for future therapeutics development.
- Published
- 2014
- Full Text
- View/download PDF
6. Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM).
- Author
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Morris LC, Nance KD, Gentry PR, Days EL, Weaver CD, Niswender CM, Thompson AD, Jones CK, Locuson CW, Morrison RD, Daniels JS, Niswender KD, and Lindsley CW
- Subjects
- Allosteric Regulation drug effects, Animals, Catalepsy chemically induced, Catalepsy drug therapy, Central Nervous System Agents therapeutic use, Drug Synergism, Exenatide, Glucagon-Like Peptide 1 pharmacology, Glucagon-Like Peptide-1 Receptor, Haloperidol, High-Throughput Screening Assays, Indoles metabolism, Indoles pharmacokinetics, Indoles pharmacology, Insulin metabolism, Insulin Secretion, Islets of Langerhans drug effects, Male, Mice, Inbred C57BL, Microsomes, Liver metabolism, Peptides pharmacology, Pyrrolidines metabolism, Pyrrolidines pharmacokinetics, Pyrrolidines pharmacology, Structure-Activity Relationship, Venoms pharmacology, Indoles chemical synthesis, Pyrrolidines chemical synthesis, Receptors, Glucagon drug effects
- Abstract
A duplexed, functional multiaddition high throughput screen and subsequent iterative parallel synthesis effort identified the first highly selective and CNS penetrant glucagon-like peptide-1R (GLP-1R) positive allosteric modulator (PAM). PAM (S)-9b potentiated low-dose exenatide to augment insulin secretion in primary mouse pancreatic islets, and (S)-9b alone was effective in potentiating endogenous GLP-1R to reverse haloperidol-induced catalepsy.
- Published
- 2014
- Full Text
- View/download PDF
7. Dihydrothiazolopyridone derivatives as a novel family of positive allosteric modulators of the metabotropic glutamate 5 (mGlu5) receptor.
- Author
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Bartolomé-Nebreda JM, Conde-Ceide S, Delgado F, Iturrino L, Pastor J, Pena MÁ, Trabanco AA, Tresadern G, Wassvik CM, Stauffer SR, Jadhav S, Gogi K, Vinson PN, Noetzel MJ, Days E, Weaver CD, Lindsley CW, Niswender CM, Jones CK, Conn PJ, Rombouts F, Lavreysen H, Macdonald GJ, Mackie C, and Steckler T
- Subjects
- Allosteric Regulation drug effects, Animals, Behavior, Animal drug effects, Dose-Response Relationship, Drug, Humans, Locomotion drug effects, Male, Rats, Receptor, Metabotropic Glutamate 5 metabolism, Structure-Activity Relationship, Antipsychotic Agents chemistry, Antipsychotic Agents pharmacology, Receptor, Metabotropic Glutamate 5 chemistry, Thiazoles chemistry, Thiazoles pharmacology
- Abstract
Starting from a singleton chromanone high throughput screening (HTS) hit, we describe a focused medicinal chemistry optimization effort leading to the identification of a novel series of phenoxymethyl-dihydrothiazolopyridone derivatives as selective positive allosteric modulators (PAMs) of the metabotropic glutamate 5 (mGlu5) receptor. These dihydrothiazolopyridones potentiate receptor responses in recombinant systems. In vitro and in vivo drug metabolism and pharmacokinetic (DMPK) evaluation allowed us to select compound 16a for its assessment in a preclinical animal screen of possible antipsychotic activity. 16a was able to reverse amphetamine-induced hyperlocomotion in rats in a dose-dependent manner without showing any significant motor impairment or overt neurological side effects at comparable doses. Evolution of our medicinal chemistry program, structure activity, and properties relationships (SAR and SPR) analysis as well as a detailed profile for optimized mGlu5 receptor PAM 16a are described.
- Published
- 2013
- Full Text
- View/download PDF
8. ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice.
- Author
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Kaufmann K, Romaine I, Days E, Pascual C, Malik A, Yang L, Zou B, Du Y, Sliwoski G, Morrison RD, Denton J, Niswender CM, Daniels JS, Sulikowski GA, Xie XS, Lindsley CW, and Weaver CD
- Subjects
- Animals, Anticonvulsants administration & dosage, Anticonvulsants chemistry, Anticonvulsants pharmacology, Calcium Signaling drug effects, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Electroshock adverse effects, HEK293 Cells, High-Throughput Screening Assays, Humans, Injections, Intraperitoneal, Mice, Microsomes, Liver metabolism, Molecular Structure, Patch-Clamp Techniques, Pentylenetetrazole toxicity, Phenylurea Compounds administration & dosage, Phenylurea Compounds chemistry, Phenylurea Compounds pharmacology, Pyrazoles administration & dosage, Pyrazoles chemistry, Pyrazoles pharmacology, Rats, Receptors, Metabotropic Glutamate drug effects, Recombinant Proteins drug effects, Seizures etiology, Valproic Acid therapeutic use, Anticonvulsants therapeutic use, G Protein-Coupled Inwardly-Rectifying Potassium Channels agonists, Phenylurea Compounds therapeutic use, Pyrazoles therapeutic use, Seizures drug therapy
- Abstract
The G-protein activated, inward-rectifying potassium (K(+)) channels, "GIRKs", are a family of ion channels (Kir3.1-Kir3.4) that has been the focus of intense research interest for nearly two decades. GIRKs are comprised of various homo- and heterotetrameric combinations of four different subunits. These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm, to effects on reward/addiction, to modulation of response to analgesics. Despite years of GIRK research, very few tools exist to selectively modulate GIRK channels' activity and until now no tools existed that potently and selectively activated GIRKs. Here we report the development and characterization of the first truly potent, effective, and selective GIRK activator, ML297 (VU0456810). We further demonstrate that ML297 is active in two in vivo models of epilepsy, a disease where up to 40% of patients remain with symptoms refractory to present treatments. The development of ML297 represents a truly significant advancement in our ability to selectively probe GIRK's role in physiology as well as providing the first tool for beginning to understand GIRK's potential as a target for a diversity of therapeutic indications.
- Published
- 2013
- Full Text
- View/download PDF
9. Identification and optimization of small molecules that restore E-cadherin expression and reduce invasion in colorectal carcinoma cells.
- Author
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Stoops SL, Pearson AS, Weaver C, Waterson AG, Days E, Farmer C, Brady S, Weaver CD, Beauchamp RD, and Lindsley CW
- Subjects
- Cadherins genetics, Cell Line, Tumor, Drug Evaluation, Preclinical methods, Epithelial-Mesenchymal Transition, Humans, RNA, Messenger metabolism, Cadherins biosynthesis, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Neoplasm Invasiveness prevention & control
- Abstract
E-cadherin is a transmembrane protein that maintains intercellular contacts and cell polarity in epithelial tissue. The down-regulation of E-cadherin contributes to the induction of the epithelial-to-mesenchymal transition (EMT), resulting in an increased potential for cellular invasion of surrounding tissues and entry into the bloodstream. Loss of E-cadherin has been observed in a variety of human tumors as a result of somatic mutations, chromosomal deletions, silencing of the CDH1 gene promoter, and proteolytic cleavage. To date, no compounds directly targeting E-cadherin restoration have been developed. Here, we report the development and use of a novel high-throughput immunofluorescent screen to discover lead compounds that restore E-cadherin expression in the SW620 colon adenocarcinoma cell line. We confirmed restoration of E-cadherin using immunofluorescent microscopy and were able to determine the EC(50) for selected compounds using an optimized In-Cell Western assay. The profiled compounds were also shown to have a minimal effect on cell proliferation but did decrease cellular invasion. We have also conducted preliminary investigations to elucidate a discrete molecular target to account for the phenotypic behavior of these small molecules and have noted a modest increase in E-cadherin mRNA transcripts, and RNA-Seq analysis demonstrated that potent analogues elicited a 10-fold increase in CDH1 (E-cadherin) gene expression.
- Published
- 2011
- Full Text
- View/download PDF
10. Discovery of N-Aryl Piperazines as Selective mGlu(5) Potentiators with Efficacy in a Rodent Model Predictive of Anti-Psychotic Activity.
- Author
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Zhou Y, Manka JT, Rodriguez AL, Weaver CD, Days EL, Vinson PN, Jadhav S, Hermann EJ, Jones CK, Conn PJ, Lindsley CW, and Stauffer SR
- Abstract
This Letter describes the discovery, SAR and in vitro and in vivo pharmacological profile of a novel non-MPEP derived mGlu(5) positive allosteric modulator (PAM) based upon an N-aryl piperazine chemotype. This mGlu(5) chemotype exhibits the ability to act as either a non-competitive antagonist/negative allosteric modulator (NAM) or potentiator of the glutamate response depending on the identity of the amide substituent, i.e., a 'molecular switch'. A rapidly optimized PAM, 10e (VU0364289), was shown to be potent and specific for the rat mGlu(5) receptor and subsequently demonstrated to be efficacious in a clinically relevant rodent model predictive of anti-psychotic activity, thus providing the first example of a centrally active mGluR(5) PAM optimized from an HTS-derived mGluR5 competitive antagonist.
- Published
- 2010
- Full Text
- View/download PDF
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