Abstract:
:The metabotropic glutamate receptor 2 (mGlu2) is a transmembrane-spanning class C G protein-coupled receptor that is an attractive therapeutic target for multiple psychiatric and neurological disorders. A key challenge has been deciphering the contribution of mGlu2 relative to other closely related mGlu receptors in mediating different physiological responses, which could be achieved through the utilization of subtype selective pharmacological tools. In this respect, allosteric modulators that recognize ligand-binding sites distinct from the endogenous neurotransmitter glutamate offer the promise of higher receptor-subtype selectivity. We hypothesized that mGlu2-selective positive allosteric modulators could be derivatized to generate bifunctional pharmacological tools. Here we developed clickable photoaffinity probes for mGlu2 based on two different positive allosteric modulator scaffolds that retained similar pharmacological activity to parent compounds. We demonstrate successful probe-dependent incorporation of a commercially available clickable fluorophore using bioorthogonal conjugation. Importantly, we also show the limitations of using these probes to assess in situ fluorescence of mGlu2 in intact cells where significant nonspecific membrane binding is evident.
journal_name
ACS Chem Neuroscijournal_title
ACS chemical neuroscienceauthors
Hellyer SD,Aggarwal S,Chen ANY,Leach K,Lapinsky DJ,Gregory KJdoi
10.1021/acschemneuro.0c00009subject
Has Abstractpub_date
2020-06-03 00:00:00pages
1597-1609issue
11issn
1948-7193journal_volume
11pub_type
杂志文章abstract::Modulation of the neuropeptide S (NPS) system has been linked to a variety of CNS disorders such as panic disorder, anxiety, sleeping disorders, asthma, obesity, PTSD, and substance abuse. In this study, a series of diphenyltetrahydro-1H-oxazolo[3,4-α]pyrazin-3(5H)-ones were synthesized and evaluated for antagonist ac...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn500113c
更新日期:2014-08-20 00:00:00
abstract::Neurons choose growth pathways with half hearted reluctance, behavior that may be appropriate to maintain fixed long lasting connections but not to regenerate them. We now recognize that intrinsic brakes on regrowth are widely expressed in these hesitant neurons and include classical tumor suppressor molecules. Here, ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章,评审
doi:10.1021/cn500110p
更新日期:2014-08-20 00:00:00
abstract::Glioblastoma (GBM) is characterized by a poor response to conventional chemotherapeutic agents, attributed to the insurgence of drug resistance mechanisms and to the presence of a subpopulation of glioma stem cells (GSCs). GBM cells and GSCs present, among others, an overexpression of antiapoptotic proteins and an inh...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.7b00023
更新日期:2018-01-17 00:00:00
abstract::Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn500103u
更新日期:2014-08-20 00:00:00
abstract::Genetically encoded tools are positioned to serve a unique and critical role in bridging the gap between the genetic identity of neurons and their functional properties. However, the use of these tools is limited by our current understanding of cell-type identity. As we make technological advances that focus on captur...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.5b00008
更新日期:2015-01-21 00:00:00
abstract::In vivo fast-scan cyclic voltammetry provides high-fidelity recordings of electrically evoked dopamine release in the rat striatum. The evoked responses are suitable targets for numerical modeling because the frequency and duration of the stimulus are exactly known. Responses recorded in the dorsal and ventral striatu...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章,评审
doi:10.1021/cn5000666
更新日期:2014-09-17 00:00:00
abstract::Pharmaceutical companies assessing the nervous system effects of candidate therapeutics often use a behavioral assay in rodents that assesses the drug's subjective (internal stimulus) effects. Variants of this so-called "drug discrimination task" have also been widely used by basic scientist for more than 50 years to ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.5b00018
更新日期:2015-03-18 00:00:00
abstract::The abnormal aggregation of α-synuclein (α-Syn) is closely associated with Parkinson's disease. Different post-translational modifications of α-Syn have been identified and contribute distinctly in α-Syn aggregation and cytotoxicity. Recently, α-Syn was reported to be N-terminally acetylated in cells, yet the function...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.7b00250
更新日期:2017-10-18 00:00:00
abstract::We report the results of computational modeling of a three-dimensional all-atom structure of the membrane-associated protein encoded by the NAT8L gene, aspartate N-acetyltransferase, which is essential for brain synthesis of N-acetyl-l-aspartate (NAA). The lack of experimentally derived three-dimensional structures of...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.0c00250
更新日期:2020-08-05 00:00:00
abstract::The clinical benzothiophene SERM (BT-SERM), raloxifene, was compared with estrogens in protection of primary rat neurons against oxygen-glucose deprivation (OGD). Structure-activity relationships for neuroprotection were determined for a family of BT-SERMs displaying a spectrum of ERα and ERβ binding affinity and agon...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn100106a
更新日期:2011-05-18 00:00:00
abstract::Ever since the discovery of its neurite growth promoting activity in sympathetic and sensory ganglia, nerve growth factor (NGF) became the prototype of the large family of neurotrophins. The use of primary cultures and clonal cell lines has revealed several distinct actions of NGF and other neurotrophins. Among severa...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.5b00069
更新日期:2015-08-19 00:00:00
abstract::The distribution and density of neurons within the brain poses many challenges when making quantitative measurements of neurotransmission in the extracellular space. A volume neurotransmitter is released into the synapse during chemical communication and must diffuse through the extracellular space to an implanted sen...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn500020s
更新日期:2015-09-16 00:00:00
abstract::1-Methyl-4-phenylpyridinium (MPP+) induces microglial activation and degeneration of dopaminergic (DAergic) neurons. Donepezil is a well-known acetylcholinesterase inhibitor used clinically to treat cognitive dysfunction in Alzheimer's disease (AD). In the present study, we tested the hypothesis that MPP+ promotes mic...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.5b00026
更新日期:2015-10-21 00:00:00
abstract::Metabolic adaptation to stress is a crucial yet poorly understood phenomenon, particularly in the central nervous system (CNS). The ability to identify essential metabolic events which predict neuronal fate in response to injury is critical to developing predictive markers of outcome, for interpreting CNS spectroscopi...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn300003r
更新日期:2012-07-18 00:00:00
abstract::SARS-CoV-2 remains a significant burden on human health. Several lines of evidence suggest that surveillance of sewage and waste can provide an early warning sign for COVID-19 recurrence in a community. In support, SARS-CoV-2 traces were found in sewage in several countries. With this in mind, it is notable that pests...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章,评审
doi:10.1021/acschemneuro.0c00312
更新日期:2020-07-01 00:00:00
abstract::Biology has inspired solutions to many engineering problems, including chemical sensing. Modern approaches to chemical sensing have been based on the biological principle of combining cross-selective chemical sensors with a pattern recognition engine to identify odors. Here, we review some recent advances made in mimi...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn200027r
更新日期:2011-05-27 00:00:00
abstract::The propagation of pathological proteins throughout the brain is the primary physiological hallmark of the progression of Alzheimer's Disease (AD). A growing body of evidence indicates that hyperphosphorylated Tau proteins are spread transcellularly between neurons in a prionlike fashion, inducing misfolding and aggre...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.0c00531
更新日期:2020-11-04 00:00:00
abstract::Parkinson's disease (PD) is the most widespread form of dementia where there is an age related degeneration of dopaminergic neurons in the substantia nigra region of the brain. Accumulation of α-synuclein (αS) protein aggregate, mitochondrial dysfunction, oxidative stress, and neuronal cell death are the pathological ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.6b00207
更新日期:2016-12-21 00:00:00
abstract::Recreational consumption of synthetic cannabinoid receptor agonists (SCRAs) is a growing crisis in public health in many parts of the world. AMB-FUBINACA is a member of this class of drugs and is responsible for a large proportion of SCRA-related toxicity both in New Zealand and internationally. Strikingly, little is ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.9b00429
更新日期:2019-10-16 00:00:00
abstract::No universally efficacious therapy exists for chronic pain, a disease affecting one-fifth of the global population. An overreliance on the prescription of opioids for chronic pain despite their poor ability to improve function has led to a national opioid crisis. In 2018, the NIH launched a Helping to End Addiction Lo...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.9b00166
更新日期:2019-06-19 00:00:00
abstract::Dendritic spines are the postsynaptic sites for the majority of excitatory synapses in the mammalian forebrain. While many spines display great stability, others change shape in a matter of seconds to minutes. These rapid alterations in dendritic spine number and size require tight control of the actin cytoskeleton, t...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn100012x
更新日期:2010-05-19 00:00:00
abstract::Chondroitin sulfate proteoglycans (CSPGs) are the most abundant components of glial scar formed after severe traumatic brain injury as well as spinal cord injury and play a crucial inhibitory role in axonal regeneration by selective contraction of filopodia of the growth cone of sprouting neurites. Healing of central ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.0c00004
更新日期:2020-02-05 00:00:00
abstract::Myasthenia gravis (MG) is an autoimmune T cell-dependent B cell-mediated disorder of the neuromuscular junction (NMJ) characterized by fluctuating skeletal muscle weakness, most commonly attributed to pathogenic autoantibodies against postsynaptic nicotinic acetylcholine receptors (AChRs). Although MG pathogenesis is ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.9b00678
更新日期:2020-03-04 00:00:00
abstract::Small hydrophobic oligomers of aggregation-prone proteins are thought to be generically toxic. Here we examine this view by perturbing an early folding contact between Phe19 and Leu34 formed during the aggregation of Alzheimer's amyloid-β (Aβ40) peptide. We find that even conservative single mutations altering this in...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.5b00074
更新日期:2015-08-19 00:00:00
abstract::We previously reported on the synthesis of substituted phenyl-4-hydroxy-1-piperidyl indole analogues with nanomolar affinity at D2 dopamine receptors, ranging from 10- to 100-fold selective for D2 compared to the D3 dopamine receptor subtype. More recently, we evaluated a panel of aripiprazole analogues, identifying s...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn300142q
更新日期:2012-12-19 00:00:00
abstract::Amyloid beta (Aβ) aggregation is the key trait responsible for the pathological devastation caused by Alzheimer's disease (AD). Among the various pathways of multifaceted toxicity exhibited by Aβ aggregates in neuronal cells, generation of reactive oxygen species (ROS) by Aβ-CuII complex and mitochondrial damage are p...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.8b00033
更新日期:2018-06-20 00:00:00
abstract::Central norepinephrine (NE) and dopamine (DA) are involved in a variety of physiological functions and behaviors. Accumulating evidence suggests that NE neurons originating from the locus coeruleus (LC) innervate DA neurons of the ventral tegmental area (VTA) and influence VTA-DA neural activity. However, the underlyi...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.7b00078
更新日期:2017-09-20 00:00:00
abstract::Artesunate is a safe noncytotoxic drug with low side effects which is used in the treatment of chloroquine-resistant malaria. In addition to being an antimalarial drug, artesunate also has immunomodulatory, anticarcinogenic, and antiviral activity. There are in vivo and in vitro studies reporting that artesunate may h...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.0c00601
更新日期:2020-12-16 00:00:00
abstract::Aggregation of hyperphosphorylated tau is the hallmark of several tauopathies, including Alzheimer's disease (AD). Although the mechanism underlying tau-associated neuronal damage remains unclear, it is believed that tau hyperphosphorylation is one of the key features in disease progression. A recent study demonstrate...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章,评审
doi:10.1021/acschemneuro.8b00632
更新日期:2019-01-16 00:00:00
abstract::Extensive experimental and computational studies have suggested that multiple Zn(2+) binding modes in amyloid β (Aβ) peptides could exist simultaneously. However, consistent results have not been obtained for the effects of Zn(2+) binding on Aβ structure, dynamics, and kinetics in particular. Some key questions such a...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn4001445
更新日期:2013-11-20 00:00:00