Publications by authors named "Jason Luther"

6 Publications

  • Page 1 of 1

Pharmacologic Characterization of AMG8379, a Potent and Selective Small Molecule Sulfonamide Antagonist of the Voltage-Gated Sodium Channel Na1.7.

J Pharmacol Exp Ther 2017 07 4;362(1):146-160. Epub 2017 May 4.

Department of Neuroscience (T.J.K., R.Y., S.A, C.P.I., M.J., D.J., J.H.L., S.G.L., J.Li., D.L., J.Lu., D.M., D.O., K.T., J.W., V.Y., D.X.D.Z., R.T.F., B.D.M.), Department of Medicinal Chemistry (M.M.W.), and Department of Pharmacokinetics and Drug Metabolism (X.B., V.B., J.R.), Amgen Inc., Cambridge, Massachusetts and Thousand Oaks, California

Potent and selective antagonists of the voltage-gated sodium channel Na1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human Na1.7 channels with an IC of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglion (DRG) neurons with an IC of 3.1 nM in whole-cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state. AMG8379 was 100- to 1000-fold selective over other Na family members, including Na1.4 expressed in muscle and Na1.5 expressed in the heart, as well as TTX-resistant Na channels in DRG neurons. Using an ex vivo mouse skin-nerve preparation, AMG8379 blocked mechanically induced action potential firing in C-fibers in both a time-dependent and dose-dependent manner. AMG8379 similarly reduced the frequency of thermally induced C-fiber spiking, whereas AMG8380 affected neither mechanical nor thermal responses. In vivo target engagement of AMG8379 in mice was evaluated in multiple Na1.7-dependent behavioral endpoints. AMG8379 dose-dependently inhibited intradermal histamine-induced scratching and intraplantar capsaicin-induced licking, and reversed UVB radiation skin burn-induced thermal hyperalgesia; notably, behavioral effects were not observed with AMG8380 at similar plasma exposure levels. AMG8379 is a potent and selective Na1.7 inhibitor that blocks sodium current in heterologous cells as well as DRG neurons, inhibits action potential firing in peripheral nerve fibers, and exhibits pharmacodynamic effects in translatable models of both itch and pain.
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http://dx.doi.org/10.1124/jpet.116.239590DOI Listing
July 2017

Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators.

Nat Struct Mol Biol 2017 02 19;24(2):108-113. Epub 2016 Dec 19.

Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, USA.

Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM-1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRα3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2.6-Å resolution. AM-3607 binds a novel allosteric site between subunits, which is adjacent to the orthosteric site where glycine binds. Our results provide new insights into the potentiation of cysteine-loop receptors by positive allosteric modulators and hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain.
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http://dx.doi.org/10.1038/nsmb.3329DOI Listing
February 2017

Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic properties.

Auton Neurosci 2009 Nov 13;151(1):46-60. Epub 2009 Sep 13.

Department of Biology, National Center for Behavioral Genomics, Brandeis University, Waltham, MA 02454, USA.

The electrical and synaptic properties of neurons are essential for determining the function of the nervous system. Thus, understanding the mechanisms that control the appropriate developmental acquisition and maintenance of these properties is a critical problem in neuroscience. A great deal of our understanding of these developmental mechanisms comes from studies of soluble growth factor signaling between cells in the peripheral nervous system. The sympathetic nervous system has provided a model for studying the role of these factors both in early development and in the establishment of mature properties. In particular, neurotrophins produced by the targets of sympathetic innervation regulate the synaptic and electrophysiological properties of postnatal sympathetic neurons. In this review we examine the role of neurotrophin signaling in the regulation of synaptic strength, neurotransmitter phenotype, voltage-gated currents and repetitive firing properties of sympathetic neurons. Together, these properties determine the level of sympathetic drive to target organs such as the heart. Changes in this sympathetic drive, which may be linked to dysfunctions in neurotrophin signaling, are associated with devastating diseases such as high blood pressure, arrhythmias and heart attack. Neurotrophins appear to play similar roles in modulating the synaptic and electrical properties of other peripheral and central neuronal systems, suggesting that information provided from studies in the sympathetic nervous system will be widely applicable for understanding the neurotrophic regulation of neuronal function in other systems.
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http://dx.doi.org/10.1016/j.autneu.2009.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765534PMC
November 2009

p75 and TrkA signaling regulates sympathetic neuronal firing patterns via differential modulation of voltage-gated currents.

J Neurosci 2009 Apr;29(17):5411-24

Department of Biology, National Center for Behavioral Genomics, Brandeis University, Waltham, Massachusetts 02454, USA.

Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) act through the tropomyosin-related receptor tyrosine kinases (Trk) and the pan-neurotrophin receptor (p75) to regulate complex developmental and functional properties of neurons. While NGF activates both receptor types in sympathetic neurons, differential signaling through TrkA and p75 can result in widely divergent functional outputs for neuronal survival, growth, and synaptic function. Here we show that TrkA and p75 signaling pathways have opposing effects on the firing properties of sympathetic neurons, and define a mechanism whereby the relative level of signaling through these two receptors sets firing patterns via coordinate regulation of a set of ionic currents. We show that signaling through the p75 pathway causes sympathetic neurons to fire in a phasic pattern showing marked accommodation. Signaling through the NGF-specific TrkA, on the other hand, causes cells to fire tonically. Neurons switch rapidly between firing patterns, on the order of minutes to hours. We show that changes in firing patterns are caused by neurotrophin-dependent regulation of at least four voltage-gated currents: the sodium current and the M-type, delayed rectifier, and calcium-dependent potassium currents. Neurotrophin release, and thus receptor activation, varies among somatic tissues and physiological state. Thus, these data suggest that target-derived neurotrophins may be an important determinant of the characteristic electrical properties of sympathetic neurons and therefore regulate the functional output of the sympathetic nervous system.
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http://dx.doi.org/10.1523/JNEUROSCI.3503-08.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326291PMC
April 2009

Nerve growth factor decreases potassium currents and alters repetitive firing in rat sympathetic neurons.

J Neurophysiol 2006 Aug 17;96(2):946-58. Epub 2006 May 17.

Department of Biology, National Center for Behavioral Genomics, Brandeis University, Waltham, Massachusetts 02454, USA.

The sympathetic nervous system is an essential regulator of the cardiovascular system and interactions with target tissue regulate sympathetic neuronal properties. The heart produces nerve growth factor (NGF), which promotes sympathetic noradrenergic innervation of cardiac tissue and affects sympathetic synaptic strength. Neurotrophins, including NGF, are important modulators of synaptic plasticity and membrane electrical properties. Here we show that acute application of NGF causes a change in the repetitive firing pattern of cultured sympathetic neurons of the rat superior cervical ganglion. Neurons fire fewer action potentials in NGF, but with increased frequency, demonstrating an NGF-dependent change from a tonic to a phasic firing pattern. Additionally, NGF decreases the spike time variance, making spikes more tightly time locked to stimulus onset. NGF causes a decrease in the amplitude of both calcium-dependent and -independent potassium currents, and inhibition of calcium-dependent potassium currents using CdCl(2) reproduces some, but not all, of the firing properties induced by NGF. This study suggests that NGF release from cardiac tissue may act to modulate the repetitive firing properties of sympathetic neurons to tune their output to meet the physiological needs of the organism.
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http://dx.doi.org/10.1152/jn.01078.2005DOI Listing
August 2006

Episodic bouts of activity accompany recovery of rhythmic output by a neuromodulator- and activity-deprived adult neural network.

J Neurophysiol 2003 Oct 2;90(4):2720-30. Epub 2003 Jul 2.

Volen Center, Brandeis University, Waltham, Massachusetts 02454, USA.

The pyloric rhythm of the stomatogastric ganglion of the crab, Cancer borealis, slows or stops when descending modulatory inputs are acutely removed. However, the rhythm spontaneously resumes after one or more days in the absence of neuromodulatory input. We recorded continuously for days to characterize quantitatively this recovery process. Activity bouts lasting 40-900 s began several hours after removal of neuromodulatory input and were followed by stable rhythm recovery after 1-4 days. Bout duration was not related to the intervals (0.3-800 min) between bouts. During an individual bout, the frequency rapidly increased and then decreased more slowly. Photoablation of back-filled neuromodulatory terminals in the stomatogastric ganglion (STG) neuropil had no effect on activity bouts or recovery, suggesting that these processes are intrinsic to the STG neuronal network. After removal of neuromodulatory input, the phase relationships of the components of the triphasic pyloric rhythm were altered, and then over time the phase relationships moved toward their control values. Although at low pyloric rhythm frequency the phase relationships among pyloric network neurons depended on frequency, the changes in frequency during recovery did not completely account for the change in phase seen after rhythm recovery. We suggest that activity bouts represent underlying mechanisms controlling the restructuring of the pyloric network to allow resumption of an appropriate output after removal of neuromodulatory input.
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http://dx.doi.org/10.1152/jn.00370.2003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557508PMC
October 2003