A5062229612- Neuroscience and Neuropharmacology Research
- Ion channel regulation and function
- Receptor Mechanisms and Signaling
- Nicotinic Acetylcholine Receptors Study
- Genetics and Neurodevelopmental Disorders
- Neuroscience and Neural Engineering
- CRISPR and Genetic Engineering
- Memory and Neural Mechanisms
- Autism Spectrum Disorder Research
- Treatment of Major Depression
- Neurotransmitter Receptor Influence on Behavior
- Pain Mechanisms and Treatments
- Cardiac electrophysiology and arrhythmias
- Botulinum Toxin and Related Neurological Disorders
- Epilepsy research and treatment
- Neural dynamics and brain function
- Attention Deficit Hyperactivity Disorder
- Parkinson's Disease Mechanisms and Treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Photoreceptor and optogenetics research
- Neurological disorders and treatments
- Neurological diseases and metabolism
- Sleep and Wakefulness Research
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Cholinesterase and Neurodegenerative Diseases
Sarepta Therapeutics (United States)
2023
Fulcrum Therapeutics (United States)
2018-2022
Bristol-Myers Squibb (United States)
2015-2019
Bristol-Myers Squibb (Germany)
2017
Wake Forest University
2009-2012
In vitro phenotypic assays of sensory neuron activity are important tools for identifying potential analgesic compounds. These typically characterized by hyperexcitable and/or abnormally, spontaneously active cells. Whereas manual electrophysiology experiments provide high-resolution biophysical data to characterize both in models and therapeutic modalities (e.g., action characteristics, the role specific ion channels, receptors), these techniques hampered their low throughput. We have...
Abstract Fragile X syndrome (FXS) is the most common genetic form of intellectual disability caused by a CGG repeat expansion in 5′‐UTR mental retardation gene FMR1 , triggering epigenetic silencing and subsequent absence protein, FMRP . Reactivation represents an attractive therapeutic strategy targeting root cause FXS. However, largely missing FXS field understanding how much reactivation required to rescue FMRP‐dependent mutant phenotypes. Here, we utilize patient‐derived excitatory...
By taking advantage of certain features in piperidine 4, we developed a novel series cyclohexylamine- and piperidine-based benzenesulfonamides as potent selective Nav1.7 inhibitors. However, compound 24, one the early analogs, failed to reduce phase 2 flinching mouse formalin test even at dose 100 mpk PO due insufficient dorsal root ganglion (DRG) exposure attributed poor membrane permeability. Two analogs with improved permeability showed much increased DRG concentrations doses 30 PO, but,...
Some epilepsies are linked to inherited traits, but many appear arise through acquired alterations in neuronal excitability. Status epilepticus (SE) is associated with numerous changes that promote spontaneous recurrent seizures (SRS), and studies have suggested hippocampal T-type Ca(2+) channels underlie increased bursts of activity integral the generation these seizures. The thalamus also contributes epileptogenesis, no directly assessed channel during SE or subsequent periods SRS. We...
3-Aryl-indole and 3-aryl-indazole derivatives were identified as potent selective Nav1.7 inhibitors. Compound 29 was shown to be efficacious in the mouse formalin assay also reduced complete Freund's adjuvant (CFA)-induced thermal hyperalgesia chronic constriction injury (CCI) induced cold allodynia models of inflammatory neuropathic pain, respectively, following intraperitoneal (IP) doses 30 mg/kg. The observed efficacy could correlated with dorsal root ganglion exposure NaV1.7 potency...
(±)-Mecamylamine is a racemic mixture of widely used brain-permeant noncompetitive inhibitor muscle-type and neuronal nicotinic receptors (NNRs). The present studies evaluated whether the stereoisomers this drug show different profiles for inhibition high-sensitivity (HS) low-sensitivity (LS) isoforms human α4β2 NNR subtype expressed in subclonal epithelial 1 cells. We found that at low concentrations (micromolar range), TC-5214 [<i>S</i>-(+)-mecamylamine] was more effective than TC-5213...
Chronic ethanol exposure produces profound disruptions in both brain rhythms and diurnal behaviors. The thalamus has been identified as a neural pacemaker of normal abnormal with low-threshold, transient (T-type) Ca(2+) channels participating this activity. We therefore examined T-type channel gene expression physiology the C57Bl/6 mice during 4-wk schedule chronic intermittent exposures vapor chamber. found that disrupts daily variations thalamic mRNA levels alters gating properties....
(<i>R</i>)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3<i>S</i>,4<i>S</i>)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen (BMS-986163) were identified from a drug discovery effort focused on development of novel, intravenous glutamate <i>N</i>-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD)....
Mechanisms of plasticity are important to the astounding capacity brain adapt and learn. Ion channels significant contributors neuronal plasticity, but their dysfunction has been implicated in several nervous system diseases from movement disorders epilepsy. Although many inherited ion channel mutations have associated with these disorders, it recently recognized that channelopathies can also include aberrant function is acquired after an insult or injury brain. These alterations being...
Background Chronic ethanol ( EtOH ) leads to disruptions in resting electroencephalogram EEG activity and sleep patterns that can persist into the withdrawal period. These have been suggested be predictors of relapse. The thalamus is a key structure involved both normal brain oscillations, such as sleep‐related abnormal rhythms found disorders epilepsy P arkinson's disease. Previously, we shown progressive changes mouse thalamic T ‐type C 2+ channels during chronic intermittent exposures...
High-throughput compound screening using electrophysiology-based assays represents an important tool for biomedical research and drug discovery programs. The recent development availability of devices capable performing high-throughput have brought the need to validate these tools by producing data that are consistent with results obtained conventional electrophysiological methods. In this study, we compared response properties hα3β4 hα4β2 nicotinic receptors their endogenous ligand...
Abstract Synucleinopathies are a group of neurodegenerative diseases characterized by the presence pathological accumulations misfolded, phosphorylated α-synuclein (αSyn) protein. Multiple lines evidence indicate that synucleinopathy disease progression is driven prion-like process transmission pathologic form αSyn. One potential therapeutic approach to prevent cell-to-cell propagation target this transmissible species with selective antibodies. In study, rodent primary neuronal culture...
Abstract Synucleinopathies such as Parkinson’s disease (PD) are characterized by pathologic production, aggregation, and cell-to-cell transmission of α-synuclein (α-syn) protein that results in impaired cellular function. While neurons the substantia nigra pars compacta express high levels highly vulnerable to its aberrant expression or conformation, brain-resident macrophages (microglia) also sensitive abnormal α-synuclein, with recent reports indicating elevated impair phagocytic ability...