Auxiliary subunits of AMPA receptors: The discovery of a forebrain-selective antagonist, LY3130481/CERC-611

Kato, Akihiko; Witkin, Jeffrey M.

doi:10.1016/j.bcp.2017.09.015

Cited by 16 publications

(8 citation statements)

References 138 publications

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“…It is composed of four subunits: GluA1, GluA2, GluA3, and GluA4, which form a heterotetramer. [ 99 – 103 ]. We have previously shown that both stressor exposure in vivo [ 62 ] and CRF exposure ex vivo [ 49 ] alter LC AMPAR signaling.…”

Section: Lc/ne Synaptic Plasticity Changes During Stressmentioning

confidence: 99%

Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System

2018

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Neural plasticity plays a critical role in mediating short- and long-term brain responses to environmental stimuli. A major effector of plasticity throughout many regions of the brain is stress. Activation of the locus coeruleus (LC) is a critical step in mediating the neuroendocrine and behavioral limbs of the stress response. During stressor exposure, activation of the hypothalamic-pituitary-adrenal axis promotes release of corticotropin-releasing factor in LC, where its signaling promotes a number of physiological and cellular changes. While the acute effects of stress on LC physiology have been described, its long-term effects are less clear. This review will describe how stress changes LC neuronal physiology, function, and morphology from a genetic, cellular, and neuronal circuitry/transmission perspective. Specifically, we describe morphological changes of LC neurons in response to stressful stimuli and signal transduction pathways underlying them. Also, we will review changes in excitatory glutamatergic synaptic transmission in LC neurons and possible stress-induced modifications of AMPA receptors. This review will also address stress-related behavioral adaptations and specific noradrenergic receptors responsible for them. Finally, we summarize the results of several human studies which suggest a link between stress, altered LC function, and pathogenesis of posttraumatic stress disorder.

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Section: Lc/ne Synaptic Plasticity Changes During Stressmentioning

confidence: 99%

Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System

2018

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“…Recently, a novel AMPA receptor antagonist, LY3130481, has been identified which selectively blocks TARP g8-containing AMPA receptors (Gardinier et al, 2016;Kato and Witkin, 2018). LY3130481 displays nanomolar potency for blockade of recombinant and native g8-containing AMPA receptors and $100-fold selectivity versus AMPA receptors associated with other g subunits or GluA subunits alone (Gardinier et al, 2016;Kato et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Modulation of TARP γ8–Containing AMPA Receptors as a Novel Therapeutic Approach for Chronic Pain

Knopp

Simmons

Guo

et al. 2019

J Pharmacol Exp Ther

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Nonselective glutamate a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptor antagonists are efficacious in chronic pain but have significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in the central nervous system (CNS). Recently, LY3130481 has been shown to selectively block AMPA receptors coassembled with the auxiliary protein, transmembrane AMPA receptor regulatory protein (TARP) g8, which is highly expressed in the hippocampus but also in pain pathways, including anterior cingulate (ACC) and somatosensory cortices and the spinal cord, suggesting that selective blockade of g8/AMPA receptors may suppress nociceptive signaling with fewer CNS side effects. The potency of LY3130481 on recombinant g8-containing AMPA receptors was modulated by coexpression with other TARPs; g2 subunits affected activity more than g3 subunits. Consistent with these findings, LY3130481 had decreasing potency on receptors from rat hippocampal, cortical, spinal cord, and cerebellar neurons that was replicated in tissue from human brain. LY3130481 partially suppressed, whereas the nonselective AMPA antagonist GYKI53784 completely blocked, AMPA receptor-dependent excitatory postsynaptic potentials in ACC and spinal neurons in vitro. Similarly, LY3130481 attenuated short-term synaptic plasticity in spinal sensory neurons in vivo in response to stimulation of peripheral afferents. LY3130481 also significantly reduced nocifensive behaviors after intraplantar formalin that was correlated with occupancy of CNS g8-containing AMPA receptors. In addition, LY3130481 dose-dependently attenuated established gait impairment after joint damage and tactile allodynia after spinal nerve ligation, all in the absence of motor side effects. Collectively, these data demonstrate that LY3130481 can suppress excitatory synaptic transmission and plasticity in pain pathways containing g8/AMPA receptors and significantly reduce nocifensive behaviors, suggesting a novel, effective, and safer therapy for chronic pain conditions. Dr. K.L.K. reports financial support (salaries) for all authors from Eli Lilly & Company, outside the submitted work. On September 26, 2016, Cerecor Inc. announced the acquisition of LY3130481 (now CERC-611) from Eli Lilly & Co. for development in patients with epilepsy. In addition, a patent WO 2015183673 A1 has been issued to Eli Lilly & Company for the molecule.

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“…Thus, on the basis of the previous and current binding and/or functional assays, the mechanism of action for AS-1 remains undefined. We can only state that the broad-spectrum anticonvulsant a Data from Rapacz et al [12] *Results showing an inhibition higher than 50% are considered to represent significant effects of the test compounds, results showing an inhibition between 25 and 50% are indicative of weak effect, and results showing an inhibition lower than 25% are not considered significant and mostly attributable to the variability of the signal around the control level receptors' function as well as the inhibition of glutamate release from the presynaptic neurons in the hippocampus (e.g., through the influence on SV2A protein of synaptic vesicles or inhibition of presynaptic voltage-gated Ca 2+ channels) [73][74][75][76][77][78]. In the aim of determination of AS-1 interaction with other binding sites on sodium channels (beyond site 2, see Table 4), we studied its influence on sodium currents in rat prefrontal cortex pyramidal neurons using the patch clamp technique.…”

Section: Discussionmentioning

confidence: 99%

N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug

et al. 2020

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In our recent studies, we identified compound N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such as the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (s.c. PTZ) test, and the 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized as a candidate for new anticonvulsant effective in different types of human epilepsy with a favorable safety margin profile determined in the rotarod test in mice. In the aim of further pharmacological evaluation of AS-1, in the current study, we examined its activity in the 6-Hz (44 mA) test, which is known as the model of drug-resistant epilepsy. Furthermore, we determined also the antiseizure activity in the kindling model of epilepsy induced by repeated injection of pentylenetetrazole (PTZ) in mice. As a result, AS-1 revealed relatively potent protection in the 6-Hz (44 mA) test, as well as delayed the progression of kindling induced by repeated injection of PTZ in mice at doses of 15 mg/kg, 30 mg/kg, and 60 mg/kg. Importantly, the isobolographic analysis showed that a combination of AS-1 and valproic acid (VPA) at the fixed ratio of 1:1 displayed a supra-additive (synergistic) interaction against PTZinduced seizures in mice. Thus, AS-1 may be potentially used in an add-on therapy with VPA. Moreover, incubation of zebrafish larvae with AS-1 substantially decreased the number, cumulative but not the mean duration of epileptiform-like events in electroencephalographic assay. Finally, the in vitro ADME-Tox studies revealed that AS-1 is characterized by a very good permeability in the parallel artificial membrane permeability assay test, excellent metabolic stability on human liver microsomes (HLMs), no significant influence on CYP3A4/CYP2D6 activity, and moderate inhibition of CYP2C9 in a concentration of 10 μM, as well as no hepatotoxic properties in HepG2 cells (concentration of 10 μM).

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Auxiliary subunits of AMPA receptors: The discovery of a forebrain-selective antagonist, LY3130481/CERC-611

Cited by 16 publications

References 138 publications

Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System

Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System

Modulation of TARP γ8–Containing AMPA Receptors as a Novel Therapeutic Approach for Chronic Pain

N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug

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