Inhibition of synaptosomal veratridine-induced sodium influx by antidepressants and neuroleptics used in chronic pain

Deffois, A.; Fage, Dominique; Carter, Christopher

doi:10.1016/s0304-3940(96)13227-4

Cited by 101 publications

(43 citation statements)

References 14 publications

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“…-channel blocker nifedipine, and NMDA-antagonist MK-801 did not show any inhibitory activity; these results are consistent with electrophysiological data reported previously (20,21 ] i assays were well correlated with the results obtained by conventional analyses previously reported (22). Activation of GABA A receptors are known to suppress the long lasting depolarization induced by 4-AP in slice preparation (23), and so the GABA A activators would be effective by this mechanism in our assay.…”

Section: +supporting

confidence: 93%

K+-Channel Openers Suppress Epileptiform Activities Induced by 4-Aminopyridine in Cultured Rat Hippocampal Neurons

et al. 2008

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Abstract. K + channels are key modulators of neuronal excitability, and mutations in certain types of these channels are known to cause epileptic seizures. Activation of K + channels is reported to suppress epileptic discharge; however, the types of K + -channel openers that are most effective as anti-epileptic agents are not well understood. We established a quantitative fluorescence assay using the Na + indicator sodium-binding benzofuran isophthalate (SBFI) for evaluation of various compounds on epileptiform activities induced by 4-aminopyridine (4-AP) in cultured rat hippocampal neurons. Among the K + -channel openers, the K V 7.2 / K V 7.3-channel openers retigabine and flupirtine and K Ca 2-channel openers NS309, DCEBIO, and 1-EBIO showed potent anti-epileptic effects similar to conventional antiepileptic drugs (AEDs). In contrast, the K Ca 1.1-channel openers NS1619, isopimaric acid, and chlorzoxazone demonstrated moderate inhibition. The K ir 6-channel openers minoxidil, cromakalim, and pinacidil did not show anti-epileptic effects. We concluded that K V 7.2 / K V 7.3, K Ca 2, and, to some extent, K Ca 1.1-channel openers, but not K ir 6-channel openers, suppress 4-AP-induced epileptiform activities in hippocampal neurons. These results suggest that the K + -channel openers for this category of K + channels might have therapeutic potential as new classes of antiepileptic drugs.

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Section: +supporting

confidence: 93%

K+-Channel Openers Suppress Epileptiform Activities Induced by 4-Aminopyridine in Cultured Rat Hippocampal Neurons

et al. 2008

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“…3). Previously, cocaine had been demonstrated to have an IC 50 of 6 M and lidocaine an IC 50 of 73.6 Ϯ 10 M as inhibitors of veratridineinduced Na ϩ flux (Matthews and Collins, 1983;Deffois et al, 1996). This potency of cocaine and lidocaine is therefore in good agreement with the data presented here.…”

Section: Methodssupporting

confidence: 92%

Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

Reith

Ali

Hashim

et al. 2012

J Pharmacol Exp Ther

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Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogs with substitutions at C-1. Here, we report on (R)-(Ϫ)-cocaine analogs with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6). Analog 2 was equipotent to cocaine as an inhibitor of the dopamine transporter (DAT), whereas 3 and 6 were 3-and 10-fold more potent, respectively. None of the analogs, however, stimulated mouse locomotor activity, in contrast to cocaine. Pharmacokinetic assays showed compound 2 occupied mouse brain rapidly, as cocaine itself; moreover, 2 and 6 were behaviorally active in mice in the forced-swim test model of depression and the conditioned place preference test. Analog 2 was a weaker inhibitor of voltage-dependent Na ϩ channels than cocaine, although 6 was more potent than cocaine, highlighting the need to assay future C-1 analogs for this activity. Receptorome screening indicated few significant binding targets other than the monoamine transporters. Benztropine-like "atypical" DAT inhibitors are known to display reduced cocaine-like locomotor stimulation, presumably by their propensity to interact with an inward-facing transporter conformation. However, 2 and 6, like cocaine, but unlike benztropine, exhibited preferential interaction with an outward-facing conformation upon docking in our DAT homology model. In summary, C-1 cocaine analogs are not cocaine-like in that they are not stimulatory in vivo. However, they are not benztropine-like in binding mechanism and seem to interact with the DAT similarly to cocaine. The present data warrant further consideration of these novel cocaine analogs for antidepressant or cocaine substitution potential.

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“…A variety of NaCh reference antagonists, as previously characterized by EP 6,23 or the Na + influx assay, 24 were tested for their ability to inhibit the response to 25 µM veratridine. Inhibition was dependent on compound concentration, except for lidocaine, which exhibited no inhibitory activity up to 66 µM (Fig.…”

Section: Resultsmentioning

confidence: 99%

State-Dependent Compound Inhibition of Nav1.2 Sodium Channels Using the FLIPR Vm Dye: On-Target and Off-Target Effects of Diverse Pharmacological Agents

Benjamin

Pruthi²,

Olanrewaju³

et al. 2006

SLAS Discovery

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Voltage-gated sodium channels (NaChs) are relevant targets for pain, epilepsy, and a variety of neurological and cardiac disorders. Traditionally, it has been difficult to develop structure-activity relationships for NaCh inhibitors due to rapid channel kinetics and state-dependent compound interactions. Membrane potential (V m ) dyes in conjunction with a high-throughput fluorescence imaging plate reader (FLIPR) offer a satisfactory 1st-tier solution. Thus, the authors have developed a FLIPR V m assay of rat Na v 1.2 NaCh. Channels were opened by addition of veratridine, and V m dye responses were measured. The IC 50 values from various structural classes of compounds were compared to the resting state binding constant (K r ) and inactivated state binding constant (K i ) obtained using patch-clamp electrophysiology (EP). The FLIPR values correlated with K i but not K r . FLIPR IC 50 values fell within 0.1-to 1.5-fold of EP K i values, indicating that the assay generally reports use-dependent inhibition rather than resting state block. The Library of Pharmacologically Active Compounds (LOPAC, Sigma) was screened. Confirmed hits arose from diverse classes such as dopamine receptor antagonists, serotonin transport inhibitors, and kinase inhibitors. These data suggest that NaCh inhibition is inherent in a diverse set of biologically active molecules and may warrant counterscreening NaChs to avoid unwanted secondary pharmacology. (Journal of Biomolecular Screening 2006: 29-39)

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Inhibition of synaptosomal veratridine-induced sodium influx by antidepressants and neuroleptics used in chronic pain

Cited by 101 publications

References 14 publications

K+-Channel Openers Suppress Epileptiform Activities Induced by 4-Aminopyridine in Cultured Rat Hippocampal Neurons

K+-Channel Openers Suppress Epileptiform Activities Induced by 4-Aminopyridine in Cultured Rat Hippocampal Neurons

Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

State-Dependent Compound Inhibition of Nav1.2 Sodium Channels Using the FLIPR Vm Dye: On-Target and Off-Target Effects of Diverse Pharmacological Agents

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