Inhibition by propofol of [<sup>3</sup>H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes

Lingamaneni, Ratnakumari; Hemmings, Hugh C.

doi:10.1111/j.1476-5381.1996.tb16064.x

Cited by 26 publications

(13 citation statements)

References 44 publications

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“…Evidence from isolated nerve terminals suggests that pharmacologically evoked glutamate release is inhibited by volatile anesthetics acting to block presynaptic voltage-gated Na ϩ channels (Ratnakumari and Hemmings, 1996;Ratnakumari et al, 2000;Lingamaneni et al, 2001). Field electrical stimulation of exocytosis in cultured hippocampal neurons depends upon voltage-gated Na ϩ channel function, because it can be blocked by tetrodotoxin, a selective antagonist of neuronal voltage-gated Na ϩ channels that prevents downstream activation of voltage-gated Ca 2ϩ channels for excitation-exocytosis coupling (T. A. Ryan, unpublished data).…”

Section: Resultsmentioning

confidence: 99%

The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis

Hemmings¹,

Yan²,

Westphalen³

et al. 2005

Mol Pharmacol

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General anesthetics have marked effects on synaptic transmission, but the mechanisms of their presynaptic actions are unclear. We used quantitative laser-scanning fluorescence microscopy to analyze the effects of the volatile anesthetic isoflurane on synaptic vesicle cycling in cultured neonatal rat hippocampal neurons monitored using either transfection of a pH-sensitive form of green fluorescent protein fused to the luminal domain of VAMP (vesicle-associated membrane protein), (synapto-pHluorin) or vesicle loading with the fluorescent dye FM 1-43. Isoflurane reversibly inhibited action potentialevoked exocytosis over a range of concentrations, with little effect on vesicle pool size. In contrast, exocytosis evoked by depolarization in response to an elevated extracellular concentration of KCl, which is insensitive to the selective Na ϩ channel blocker tetrodotoxin, was relatively insensitive to isoflurane.Inhibition of exocytosis by isoflurane was resistant to bicuculline, indicating that this presynaptic effect is not caused by the well known GABA A receptor modulation by volatile anesthetics. Depression of exocytosis was mimicked by a reduction in stimulus frequency, suggesting a reduction in action potential initiation, conduction, or coupling to Ca 2ϩ channel activation. There was no evidence for a direct effect on endocytosis. The effects of isoflurane on synaptic transmission are thus caused primarily by inhibition of action potential-evoked synaptic vesicle exocytosis at a site upstream of Ca 2ϩ entry and exocytosis, possibly as a result of Na ϩ channel blockade and/or K ϩ channel activation, with the possibility of lesser contributions from Ca 2ϩ channel blockade and/or soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated vesicle fusion.

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Section: Resultsmentioning

confidence: 99%

The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis

Hemmings¹,

Yan²,

Westphalen³

et al. 2005

Mol Pharmacol

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“…Inhibition of specifically bound [ 3 H]-BTX-B has served as a facile method to evaluate whether a compound has interaction with site 2 on the sodium channel protein [7]. …”

Section: Methodsmentioning

confidence: 99%

“…More recent studies suggest that propofol effects on Na channels could play a major role in its mechanism of action. Propofol has been shown to displace [ 3 H]-BTX-B binding from sodium channels in rat synaptoneurosomes [7] and inhibit veratridine-evoked sodium influx in rat synaptoneurosomes [8]. In electrophysiology studies, propofol has been shown to inhibit sodium currents from isolated rat neurohypophysial nerve terminals [9].…”

Section: Introductionmentioning

confidence: 99%

Comparative molecular field analysis and synthetic validation of a hydroxyamide-propofol binding and functional block of neuronal voltage-dependent sodium channels

Brown

Eidam

Paige

et al. 2009

Bioorganic & Medicinal Chemistry

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Voltage gated sodium channels represent an important therapeutic target for a number of neurological disorders including epilepsy. Unfortunately, medicinal chemistry strategies for discovering new classes of antagonist for trans-membrane ion channels have been limited to mostly broad screening compound arrays. We have developed new sodium channel antagonist based on a propofol scaffold using the ligand based strategy of comparative molecular field analysis (CoMFA). The resulting CoMFA model was correlated and validated to provide insights into the design of new antagonists and to prioritize synthesis of these new structural analogues (compounds 4 and 5) that satisfied the steric and electrostatic model. Compounds 4 and 5 were evaluated for [3H]-batrachotoxinin-A-20-α-benzoate ([3H]-BTX-B) displacement yielding IC50's of 22 and 5.7 μM, respectively. We further examined the potency of these two compounds to inhibit neuronal sodium currents recorded from cultured hippocampal neurons. At a concentration of 50 μM, compounds 4 and 5 tonically inhibited sodium channels currents by 59 ± 7.8% (n=5) and 70 ± 7.5% (n=7) respectively. This clearly demonstrates that these compounds functionally antagonize native neuronal sodium channel currents. In summary, we have shown that CoMFA can be effectively used to discover new classes of sodium channel antagonists.

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“…µM half-maximally inhibited the function of the sodium channel from human brain cortex incorporated into a voltage-clamped planar lipid bilayer [51]. By using a neurochemical approach, Ratnakumari and Hummings [52] reported that propofol (10-200 µM) concentrationdependently inhibited [ 3 H]batrachotoxinin-A 20-α-benzoate binding to sodium channels, with an IC 50 value of 26 µM. In the same study, it was shown that propofol inhibited veratridine-evoked Na + influx with an IC 50 value of 46 µM.…”

Section: Anticonvulsant and Anxiolytic Effectsmentioning

confidence: 99%

Propofol in Anesthesia. Mechanism of Action, Structure-Activity Relationships, and Drug Delivery

Trapani¹,

Altomare²,

Sanna³

et al. 2000

CMC

343

209

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Propofol (2,6-diisopropylphenol) is becoming the intravenous anesthetic of choice for ambulatory surgery in outpatients. It is extensively metabolized, with most of the administered dose appearing in the urine as glucuronide conjugates. Favorable operating conditions and rapid recovery are claimed as the main advantages in using propofol, whereas disadvantages include a relatively high incidence of apnea, and blood pressure reductions. Besides a literature summary of the pharmacodynamics, pharmacokinetics, toxicology, and clinical use, this review provides a deeper discussion on the current understanding of mechanism of action and structure-activity relationships, and recent findings on drug delivery technologies as applied to the improvement of propofol formulations. The action of propofol involves a positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABAA receptors. Recent results from recombinant human GABAA receptor experiments and findings from the work exploring the effects at other receptors (e.g., glycine, nicotinic, and M1 muscarinic receptors) are reviewed. Studies showing its antiepileptic and anxiolytic properties are also discussed. The structure-activity relationships (SAR) of series of alkylphenols and p-X-substituted congeners have been reinvestigated. Interestingly, unlike the other congeners tested sofar, p-iodo-2,6-diisopropylphenol displayed anticonvulsant and anticonflict effects, but not sedative-hypnotic and anesthetic properties. Due to its high lipid-solubility, propofol was initially formulated as a solution with the surfactant Cremophor EL, but the occurrence of pain on injection and anaphylactoid reactions prompted to search for alternative formulations. Results from using cyclodextrins, water-soluble prodrugs, and adopting Bodor's approach to the site-specific chemical delivery system (CDS), as well as the advantages provided by computer-controlled infusion systems, are examined in some detail.

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Inhibition by propofol of [³H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes

Cited by 26 publications

References 44 publications

The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis

The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis

Comparative molecular field analysis and synthetic validation of a hydroxyamide-propofol binding and functional block of neuronal voltage-dependent sodium channels

Propofol in Anesthesia. Mechanism of Action, Structure-Activity Relationships, and Drug Delivery

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Inhibition by propofol of [3H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes

Cited by 26 publications

References 44 publications

The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis

The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis

Comparative molecular field analysis and synthetic validation of a hydroxyamide-propofol binding and functional block of neuronal voltage-dependent sodium channels

Propofol in Anesthesia. Mechanism of Action, Structure-Activity Relationships, and Drug Delivery

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Inhibition by propofol of [³H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes