Nav1.2 channel blocker | BIII 890CL (crobenetine)

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Target protein: 
Nav1.2
Probe Name: 
BIII 890CL
MOLECULAR WEIGHT [DA]: 
416.01 (HCl salt)
In stock: 
185

Chemical structure

Highlights

BIII 890CL is a highly potent, selective, use- and voltage-dependent sodium channel blocker that can be used as tool compound to test biological hypotheses in vitro and in vivo. The compound has a high selectivity for site 2 of the sodium channel and preferentially binds to the inactivated state of the channel with an IC50 of 77 nM based on patch clamp evaluations. In contrast, the binding at the resting state is only 18 µM. This exceptional selectivity of more than 230 fold for the different states of the sodium channel makes this compound unique compared with other sodium channel blockers.1-4 Therefore, BIII 890CL is able to discriminate between highly (over)activated, depolarized neurons and neurons with physiological membrane potentials.

In animal studies such as the maximum electrical shock model it could be demonstrated that the compound supresses tonic seizures at doses which do not interfere with physiological functions of the sodium channel.

With BI-55CL we also offer a structurally close analogue with more than 1000 fold lower potency for site 2 of the sodium channel (Ki ~ 10 µM; [3H]-BTX). Although the selectivity between the two states of the sodium channel has not been fully determined, the compound can be used as a comparator compound in in vitro studies.1-4

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Target information

The voltage-gated sodium (Nav) channels are responsible for the rapid rising phase of an action potential, and thus play an essential role in membrane excitability and electrical signalling.

Three distinct functional states are known: resting, active, and inactivated and all play a key role in neuronal activation. They are highly selective for the transport of sodium ions across cell membranes and become activated by a change in transmembrane voltage which is initially negatively charged. The activation results in a sodium influx and further depolarization of the neuron as the cause for an action potential. At the peak of the action potential, the sodium channels inactivate themselves by closing their inactivation gate. The neuron has to repolarize to its resting potential to bring the sodium channel back into the resting state.1,2,4

Sodium channels play a major role in signal propagation within the PNS and CNS but also in cardiac myocytes. Mutations that interfere with Na+ channel inactivation can contribute to cardiovascular diseases or epileptic seizures by over-excitation of muscle or nerve cells.1,2,4

Cryo-EM structure of Nav1.2 in complex with cynotoxin KIIIA(X. Oan et al.).

Figure 3: Cryo-EM structure of Nav1.2 in complex with cynotoxin KIIIA (X. Pan et al.).5

In vitro Activity

Probe name / Negative control

BIII 890CL

BI-55CL

MW [Da]

416.0 (HCl salt)

339.9 (HCl salt)

Displacement of [3H]BTX Ki [nM]

BTX: batrachotoxina

43

>10.000

Inhibition of veratridine induced glutamate release in rat brain slices IC50 [nM]a

322

n.d.

a for detailed assay conditions see reference 3

In vitro DMPK and CMC parameters

Probe name / Negative control

BIII 890CL

BI-55CL

Melting point (°C)

258

n.d.

logP (pH 10)

3.3

n.d.

Solubility @ pH 4 / pH 6 / pH 7 [µg/ml]

2560 / 1040 / 8

n.d.

CACO permeability @pH7.4 [*10-6 cm/s]

n.d.

tbd

CACO efflux ratio

n.d.

tbd

Microsomal stability (human) [% QH]

87

n.d.

Hepatocyte stability (human/mouse/rat) [% QH]

n.d.

n.d.

Plasma protein binding (rat) [%]

99.2

n.d.

hERG [inh. % @ 1 µM]

54

n.d.

CYP 3A4 (IC50) [µM]

11.4

n.d.

CYP 1A2 (IC50) [µM]

25.5

n.d.

CYP 2C9 (IC50) [µM]

6.9

n.d.

CYP 2C19 (IC50) [µM]

2.3

n.d.

CYP 2D6 (IC50) [µM]

0.03

n.d.

In vivo DMPK parameters

BIII 890CL

RAT

tmax [h]a

2.83

Cmax [nM]a

1.51

AUC [nM]a

24

a Oral dose: 3 mg/kg

In vivo pharmacology

Maximum electroshock (MES) test in mice ID50 = 6.1 mg/kg.3

Negative control

MOLECULAR WEIGHT OF NEGATIVE CONTROL [DA]: 
339.91 (HCl salt)

With BI-55CL we offer a structurally close analogue with more than 1000 fold lower potency for site 2 of the sodium channel (Ki ~ 10 µM; [3H]-BTX).

BI-55CL which serves as a negative control

Figure 4: BI-55CL which serves as a negative control

Selectivity

BIII 890CL

Selectivity data available

Cerep®

No

Eurofins-Panlabs®

Yes

Invitrogen®

No

DiscoverX

No

Dundee

No

 

Download selectivity data: 

reference molecules

For a review on voltage-gated sodium channel blockers please see reference 6.

Summary

BIII 890CL is a highly potent, selective and use-dependent voltage-dependent sodium channel blocker suitable for in vitro and in vivo biological experiments. The compound has a high selectivity for site 2 of the sodium channel and preferentially binds to the inactivated state of the channel with an IC50 of 77 nM based on patch clamp evaluations. In contrast, the binding at the resting state is only 18 µM. This exceptional selectivity of more than 230 fold for the different states of the sodium channel makes this compound unique compared with other sodium channel blockers.1-3 Therefore, BIII 890CL is able to discriminate between highly (over)activated, depolarized neurons and neurons with physiological membrane potentials.
In animal studies such as the maximum electrical shock model it could be demonstrated that the compound supresses tonic seizures at doses which do not interfere with physiological functions of the sodium channel.
With BI-55CL we also offer a structurally close analogue with more than 1000 fold lower potency for site 2 of the sodium channel (Ki ~ 10 µM; [3H]-BTX). Although the selectivity between the two states of the sodium channel has not been fully determined, the compound can be used as a comparator compound in in vitro studies.

Supplementary data

References

  1. Potent blockade of sodium channels and protection of brain tissue from ischemia by BIII 890CL

    Adrian J. Carter, Matthias Grauert, Uwe Pschorn, Wolf Dietrich Bechtel, Christina Bartmann-Lindholm, Yusheng Qu, Todd Scheuer, William A. Catterall, and Thomas Weiser

    Proceedings of the National Academy of Sciences of the United States of America 2000, 97, 4944-4949.

  2. Analgesic activity of a novel use-dependent sodium channel blocker, crobenetine, in mono-arthritic rats

    J. M. A. Laird, A. J. Carter, M. Grauert, F. Cervevo

    British Journal or Pharmacology 2001, 134, 1742-1748.

  3. Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as use-dependent sodium channel blockers for the treatment of stroke

    Matthias Grauert, Wolf. D. Bechtel, Thomas Weiser, Werner Stransky, Herbert Nar, Adrian J. Carter

    J. Med. Chem. 2002, 45, 3755-3764.

  4. The importance of voltage-dependent sodium channels in cerebral ischaemia

    Adrian J. Carter

    Amino Acids 1998, 14, 159-169.

  5. Molecular basis for pore blockade of human Na+ channel Nav1.2 by the μ-conotoxin KIIIA

    Xiaojing Pan, Zhangqiang Li, Xiaoshuang Huang, Gaoxingyu Huang, Shuai Gao, Huaizong Shen, Lei Liu, Jianlin Le, Nieng Yan

    Science 2019, 10.1126/science.aaw2999.

  6. Voltage-Gated Sodium Channel Blockers; Target Validation and Therapeutic Potential

    John N. Wood, James Boorman

    Current Topics in Medicinal Chemistry 2005, 5, 529-537.

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