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(-)-Bicuculline methochloride (l-Bicuculline methochloride), an enantiomer of (+)-bicuculline methochloride, is a highly potent GABAA receptor antagonist. (-)-Bicuculline methochloride blocks afterhyperpolarizations (AHPs) mediated by Ca2+-activated K+ channels in various types of neurons.
| Targets |
GABAA receptor
|
|---|---|
| ln Vitro |
Bicuculline itself is difficult to use because it is unstable at physiological pH (Ref. 8) and not very soluble in aqueous solutions. This can be a problem, particularly for iontophoresis and superfusion of in vitro preparations and so, in response to this, the quaternary N-methyl derivative was synthesized and various salts (bicuculline methiodide, methochloride and methobromide, which we will refer to as BIC salts) were made available. The base of bicuculline and BIC salts was used extensively as specific GABAA receptor antagonists. It should be noted that recent experiments using recombinant receptors have modified the classical view of the interaction of bicuculline and SR95531 with the GABAA receptor. Indeed, it has been suggested that both compounds might have a negative allosteric effect (i.e. be inverse agonists) rather than (or in addition to) being competitive antagonists.
Several reports have shown that bicuculline and BIC salts also affect other neurotransmitter systems (e.g. the cholinergic system) and possibly ion channels, but results from these studies, which are summarized in Table 1, have been overlooked by many investigators. There appear to be two main reasons for this. First, actions on the cholinergic system should be easily distinguished from the GABAergic effect (for example, block of nicotinic responses will have an inhibitory effect instead of the classical excitatory effect of bicuculline) and second, some of the drugs' effects (e.g. effects on spinal cord neurones) occurred at rather high concentrations [1]. |
| ln Vivo |
(-)-Bicuculline memethochide (0.6 nmol/rat) attenuates Neurotropin's anti-allodynic effect [2]. IV (50-100 NU/kg) doses of Neurotropin elicited an antiallodynic action in L5-SNL rats. Moreover, intracerebroventricular (400 mNU/rat), but not intrathecal, injection of Neurotropin inhibited allodynia. The antiallodynic action of Neurotropin (100 NU/kg, IV) was antagonized by intrathecal injections of yohimbine (10 nmol/rat), ketanserin (30 nmol/rat), MDL72,222(30 nmol/rat), bicuculline (0.6 nmol/rat) and CGP35348 (30 nmol/rat). On the other hand, the antiallodynic action of intrathecally injected m-CPBG (5-HT(3) receptor agonist) was reversed by intrathecal injection of bicuculline and CGP35348, suggesting interaction of 5-HT(3) receptors and spinal inhibitory (GABAergic) interneurons.
Conclusions: These results suggest that the antiallodynic effect of Neurotropin is mediated via activation of descending pain inhibitory systems, such as the noradrenergic and serotonergic systems, which project from supraspinal sites to the spinal dorsal horn. In addition, activation of inhibitory GABAergic interneurons via 5-HT(3) receptors by serotonin released in the spinal dorsal horn may also be involved in the antiallodynic action of Neurotropin [2].
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| Cell Assay |
Block of Ca2+-activated K+ currents by BIC salts (bicuculline methiodide, methochloride and methobromide) in mammalian neurones. These experiments were performed on brain slices using either intracellular recordings (a, b) or whole-cell patch-clamp recordings (c). a: Concentration-dependent blockade of the apamin-sensitive afterhyperpolarization (AHP) by a BIC salt in a mesencephalic dopaminergic neurone. Note that the maximal effect of bicuculline methochloride (BMC) is similar to the one of a maximally active concentration of apamin. b: Comparison of the potency of BMC as a GABAA receptor antagonist (circles) and as a blocker of the AHP (squares) in dopaminergic neurones. The antagonism at GABAA receptors was estimated by the ability of the BIC salts to antagonize the increase in conductance induced by muscimol (3 μm) (not shown). Note that the two curves partially overlap. c: Concentration-dependent enhancement by a BIC salt of the rebound low-threshold spike in a thalamic reticular nucleus neurone. This effect is due to a block of the apamin-sensitive current. Note that it occurs at concentrations similar to the ones that block this current in dopaminergic neurones [1].
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| Animal Protocol |
Animal/Disease Models: Rat L5-SNL model [2]
Doses: 0.6 nmol/rat Route of Administration: Intrathecal injection (100 NU/kg, intravenous (iv) (iv)injection) 5 minutes before administering Neurotropin Experimental Results:Attenuated the anti-allodynic effect of Neurotropin . The left fifth lumbar nerve of rats was tightly ligated with silk sutures under pentobarbital anesthesia. Mechanical allodynia was confirmed by measuring the hindpaw withdrawal threshold in response to application of von Frey filaments. Behavioral tests were performed at 28 days after nerve ligation. Neurotropin was administered IV, intrathecally or intracerebroventricularly in L5 spinal nerve ligation (L5-SNL) rats. We examined the effects of noradrenergic, serotonergic and gamma-aminobutyric acid (GABA)ergic antagonists on the antiallodynic action of Neurotropin in L5-SNL rats. Yohimbine hydrochloride (yohimbine) was used as an alpha(2) adrenoceptor antagonist, ketanserin tartrate (ketanserin) as a 5-HT(2A) receptor antagonist, MDL72,222 as a 5-HT(3) receptor antagonist, (-)-bicuculline methobromide (bicuculline) as a GABA(A) receptor antagonist, and CGP35,348 as a GABA(B) receptor antagonist, and intrathecally injected. [2] |
| References |
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| Additional Infomation |
Neurotropin, a nonprotein extract isolated from inflamed skin of rabbits inoculated with vaccinia virus, is widely used in Japan to treat chronic pain such as neuropathic pain. Although some studies have been conducted on the mechanism of the antiallodynic action of Neurotropin, this mechanism has yet to be adequately clarified.[2]
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| Molecular Formula |
C₂₁H₂₀CLNO₆
|
|---|---|
| Molecular Weight |
417.8396
|
| Exact Mass |
417.098
|
| CAS # |
53552-05-9
|
| Related CAS # |
(-)-Bicuculline methobromide;73604-30-5;Bicuculline methiodide;40709-69-1;Bicuculline;485-49-4
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| PubChem CID |
56972147
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
0
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
1
|
| Heavy Atom Count |
29
|
| Complexity |
655
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| Defined Atom Stereocenter Count |
2
|
| SMILES |
C[N+]1(CCC2=CC3=C(C=C2C1C4C5=C(C6=C(C=C5)OCO6)C(=O)O4)OCO3)C.[Cl-]
|
| InChi Key |
RLJKFAMYSYWMND-VOMIJIAVSA-M
|
| InChi Code |
InChI=1S/C21H20NO6.ClH/c1-22(2)6-5-11-7-15-16(26-9-25-15)8-13(11)18(22)19-12-3-4-14-20(27-10-24-14)17(12)21(23)28-19/h3-4,7-8,18-19H,5-6,9-10H2,1-2H31H/q+1/p-1/t18-,19+/m1./s1
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| Chemical Name |
(5R)-5-[(6S)-6,8-dihydro-8-oxofuro[3,4-e]-1,3-benzodioxol-6-yl]-5,6,7,8-tetrahydro-6,6-dimethyl-1,3-dioxolo[4,5-g]isoquinolinium,
monochloride
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| Synonyms |
l-Bicuculline methochloride (−)-Bicuculline methochloride
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3933 mL | 11.9663 mL | 23.9326 mL | |
| 5 mM | 0.4787 mL | 2.3933 mL | 4.7865 mL | |
| 10 mM | 0.2393 mL | 1.1966 mL | 2.3933 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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