A Disubstituted Succinamide Is a Potent Sodium Channel Blocker with Efficacy in a Rat Pain Model

Priest, Birgit T.; García, María L.; Middleton, Richard E.; Brochu, Richard M.; Clark, Samantha; Dai, Ge; Dick, Ivy E.; Felix, John P.; Liu, Chou J.; Reiseter, Brita S.; Schmalhofer, William A.; Shao, Pengcheng P.; Tang, Yui S.; Chou, Margaret Z; Köhler, Martin; Smith, McHardy M.; Warren, Vivien A.; Williams, Brande S.; Cohen, Charles J.; Martin, William J.; Meinke, Peter T.; Parsons, William H.; Wafford, Keith A.; Kaczorowski, Gregory J.

doi:10.1021/bi0493259

Cited by 32 publications

(21 citation statements)

References 41 publications

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“…A high-throughput screening campaign discovered the novel sodium channel blocker N-{ [2Ј-(aminosulfonyl)biphenyl-4-yl]methyl}-NЈ-(2,2Ј-bithien-5-ylmethyl)succinamide (Priest et al, 2004). N-{[2Ј-(Aminosulfonyl)biphenyl-4-yl]-methyl}-NЈ-(2,2Ј-bithien-5-ylmethyl)succinamide had efficacy in an animal model of tonic pain, but its poor pharmacokinetic profile prohibited further in vivo characterization.…”

Section: Resultsmentioning

confidence: 99%

Block of Peripheral Nerve Sodium Channels Selectively Inhibits Features of Neuropathic Pain in Rats

Brochu¹,

Dick²,

Tarpley³

et al. 2005

Mol Pharmacol

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Several sodium channel blockers are used clinically to treat neuropathic pain. However, many patients fail to achieve adequate pain relief from these highly brain-penetrant drugs because of dose-limiting central nervous system side effects. Here, we describe the functional properties of trans-N-{[2Ј-(aminosulfonyl)biphenyl-4-yl]methyl}-N-methyl-NЈ-[4-(trifluoromethoxy)benzyl]cyclopentane-1,2-dicarboxamide (CDA54), a peripherally acting sodium channel blocker. In whole-cell electrophysiological assays, CDA54 blocked the inactivated states of hNa V 1.7 and hNa V 1.8, two channels of the peripheral nervous system implicated in nociceptive transmission, with affinities of 0.25 and 0.18 M, respectively. CDA54 displayed similar affinities for the tetrodotoxin-resistant Na ϩ current in small-diameter mouse dorsal root ganglion neurons. Peripheral nerve injury causes spontaneous electrical activity in normally silent sensory neurons. CDA54 inhibited these injury-induced spontaneous action potentials at concentrations 10-fold lower than those required to block normal A-and C-fiber conduction. Consistent with the selective inhibition of injury-induced firing, CDA54 (10 mg/kg p.o.) significantly reduced behavioral signs of neuropathic pain in two nerve injury models, whereas the same dose of CDA54 did not affect acute nociception or motor coordination. In anesthetized dogs, CDA54, at plasma concentrations of 6.7 M, had no effect on cardiac electrophysiological parameters including conduction. Thus, the peripheral nerve sodium channel blocker CDA54 selectively inhibits sensory nerve signaling associated with neuropathic pain.

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Section: Resultsmentioning

confidence: 99%

Block of Peripheral Nerve Sodium Channels Selectively Inhibits Features of Neuropathic Pain in Rats

Brochu¹,

Dick²,

Tarpley³

et al. 2005

Mol Pharmacol

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“…The remaining radioactivity on the filter was quantitated using a TopCount (Packard Instruments). Specific binding was defined as the difference between total and nonspecific binding in the presence of 5 mM BPBTS [Priest et al, 2004].…”

Section: Off-target Activity Screenmentioning

confidence: 99%

Pharmacological efficacy and safety profile of taranabant in preclinical species

Fong

Shearman

Stribling

et al. 2009

Drug Development Research

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Taranabant is a highly selective and potent cannabinoid CB 1 receptor inverse agonist. We compared the pharmacological properties of taranabant with another inverse agonist, rimonabant, and determined the preclinical safety margins of taranabant. In vitro studies demonstrated that taranabant is $10-fold more potent than rimonabant at the CB 1 receptor, and taranabant is more selective based on offtarget in vitro screening. In vivo efficacy studies demonstrated that taranabant is $10-fold more potent than rimonabant in diet-induced obese rats. In repeat-dose toxicological studies, taranabant did not cause mortality in rodents and monkeys at exposure margins r6478 and 1922 times the estimated human exposure at 0.5 mg/day À1 . Taranabant did not produce CNS signs, including seizures, when administered to monkeys for 1 year at 10 mg/kg À1 day À1 (highest dose tested chronically), corresponding to an exposure margin of 974 times. In contrast to primates, taranabant produced brief handling-induced seizure-like activity in rodents, species predisposed to handling-induced seizures. Throughout the entire preclinical program, taranabant did not cause histopathological changes in the peripheral or central nervous system. In summary, the highly selective nature of taranabant is consistent with its generally favorable preclinical safety profile. Drug Dev Res 70 : 349-362, 2009. r

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“…Thereafter, both apical and basolateral compartments were washed three times with PBS, and the transwell filter was cut out and its associated radioactivity determined using a ␤-counter. Data from saturation, competition and ligand dissociation experiments were analyzed as described previously (Knaus et al, 1995;Priest et al, 2004 Cloning of Dog NPC1L1 and Expression in MDCKII Cells. Total RNA was isolated from 3 ϫ 10 7 MDCKII cells using TriReagent and purified with RNeasy columns.…”

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confidence: 99%

Madin-Darby Canine Kidney II Cells: A Pharmacologically Validated System for NPC1L1-Mediated Cholesterol Uptake

Weinglass

Köhler²,

Nketiah³

et al. 2008

Mol Pharmacol

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Absorption of dietary cholesterol in the proximal region of the intestine is mediated by Niemann-Pick C1-like protein (NPC1L1) and is sensitive to the cholesterol absorption inhibitor ezetimibe (EZE). Although a correlation exists between EZE binding to NPC1L1 in vitro and efficacy in vivo, the precise nature of interaction(s) between NPC1L1, EZE, and cholesterol remain unclear. Here, we analyze the direct relationship between EZE analog binding to NPC1L1 and its influence on cholesterol influx in a novel in vitro system. Using the EZE analog [ 3 H]AS, an assay that quantitatively measures the expression of NPC1L1 on the cell surface has been developed. It is noteworthy that whereas two cell lines (CaCo-2 and HepG2) commonly used for studying NPC1L1-dependent processes express almost undetectable levels of NPC1L1 at the cell surface, polarized Madin-Darby canine kidney (MDCKII) cells endogenously express 4 ϫ 10 5 [ 3 H]AS sites/ cell under basal conditions. Depleting endogenous cholesterol with the HMG CoA reductase inhibitor lovastatin leads to a 2-fold increase in the surface expression of NPC1L1, supporting the contention that MDCKII cells respond to changes in cholesterol homeostasis by up-regulating a pathway for cholesterol influx. However, a significant increase in surface expression levels of NPC1L1 is necessary to characterize a pharmacologically sensitive, EZE-dependent pathway of cholesterol uptake in these cells. Remarkably, the affinity of EZE analogs for binding to NPC1L1 is almost identical to the IC 50 blocking cholesterol flux through NPC1L1 in MDCKII cells. From a mechanistic standpoint, these observations support the contention that EZE analogs and cholesterol share the same/overlapping binding site(s) or are tightly coupled through allosteric interactions.

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A Disubstituted Succinamide Is a Potent Sodium Channel Blocker with Efficacy in a Rat Pain Model

Cited by 32 publications

References 41 publications

Block of Peripheral Nerve Sodium Channels Selectively Inhibits Features of Neuropathic Pain in Rats

Block of Peripheral Nerve Sodium Channels Selectively Inhibits Features of Neuropathic Pain in Rats

Pharmacological efficacy and safety profile of taranabant in preclinical species

Madin-Darby Canine Kidney II Cells: A Pharmacologically Validated System for NPC1L1-Mediated Cholesterol Uptake

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