Ganstigmine
Ganstigmine is a potent, orally active, blood-brain barrier-permeable acetylcholinesterase (AChE) inhibitor, with an IC50 value of 65 nM against human AChE, 310 nM against human butyrylcholinesterase (BChE), and 5.12 μM against Torpedo californica AChE. Ganstigmine covalently binds to the serine residue at the active site of Torpedo californica AChE, and the nitrogen atom on its moiety forms a key hydrogen bond interaction with the histidine residue (His440) at the active site, inactivating the catalytic triad. Ganstigmine increases extracellular acetylcholine levels in the brain of rodents without altering the concentrations of other neurotransmitters, stimulates cholinergic transmission, and induces the release of soluble non-amyloidogenic amyloid precursor protein. Ganstigmine exhibits neuroprotective activity independent of cholinesterase inhibition, prevents neuronal death, alleviates β-amyloid-induced neurodegeneration, rescues cholinergic neuron loss, and reverses scopolamine-induced amnesia and memory deficits. Ganstigmine shows cholinesterase inhibition-independent neuroprotective effects against growth factor deprivation and Aβ25-35 toxicity. Ganstigmine can be used in research on Alzheimer's disease, cholinergic dysfunction, and neuroprotection.
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- CAS. Nr.: 457075-21-7
- Formel: C22H27N3O3
- Molecular Weight:381.47
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Speicherung:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biologische Aktivität
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Chemical Information
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Help & FAQs
Biologische Aktivität
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hAChE 65 nM (IC50) |
hBCHE 310 nM (IC50) |
Ganstigmine (CHF 2819 (free base)) inhibits Torpedo californica acetylcholinesterase in vitro, with an IC50 of 5.12 μM[1].
Ganstigmine inhibits human erythrocyte AChE and human plasma BChE with IC50 values of 65 nM and 310 nM, respectively, and exhibits approximately 5-fold selectivity for AChE[2].
Ganstigmine (1-10 μM; 8 days) exerts a dose-dependent neuroprotective effect on primary cortical neurons from 9-day-old chick embryos, antagonizes cell death induced by growth factor deprivation, and reaches its peak efficacy at 3 μM (increasing cell viability by nearly 3-fold)[3].
Ganstigmine (0.1-3 μM; administered from day 1 until the end of the 48-hour β-amyloid25-35 treatment) protects primary cortical neurons derived from chick embryos against β-amyloid25-35-induced neurotoxic damage, increasing neuronal survival rate to 74.4% of that in the undamaged control group (protecting 50% of neurons)[3].
Ganstigmine protects primary chicken cortical neurons against β-amyloid-induced toxic injury via a mechanism independent of cholinesterase inhibition[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Primary chicken embryonic cortical neurons, E9
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Concentration:1, 3, 10 μM
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Incubation Time:8 days
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Result:Prevented progressive neuronal death induced by growth factor deprivation under 2% fetal calf serum conditions.
Increased neuronal survival by nearly 3-fold at 3 μM.
Produced weaker neuroprotective effects at 1 and 10 μM.
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Cell Line:Primary chicken embryonic cortical neurons, E8
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Concentration:0.1-3 μM
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Incubation Time:added from day 1; Aβ25-35 at 10 μM was added for the final 48 h
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Result:Increased neuronal viability to 74.4% of the unlesioned control level.
Protected approximately 50% of neurons from Aβ25-35-induced toxicity.
Concentrations of 10 μM and above caused additional neuronal damage in the Aβ lesion model.
Ganstigmine (0.001-3 mg/kg; administered via reverse dialysis using a microdialysis probe; p.o.; single dose; once daily for 6 consecutive days; 20 min perfusion) selectively increases extracellular acetylcholine concentrations in the prefrontal cortex of rats via local and oral administration (including repeated dosing). Specifically, the 3 mg/kg p.o. dose reverses scopolamine-induced habituation impairment and memory deficits without affecting other neurotransmitter systems[5].
Ganstigmine (1.5 mg/kg; p.o.; single administration) is a centrally selective acetylcholinesterase (AChE) inhibitor in rats. Its oral ED50 for inhibiting AChE in rat brain is 1.5 mg/kg, and it shows extremely low peripheral (cardiac) activity[5].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:AD11 anti-NGF transgenic mice[4]
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Dosage:3 mg/kg/d; 6 mg/kg/d
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Administration:i.p.; daily; 3 weeks; p.o.; daily; 4 months
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Result:Rescued the loss of cholinergic (ChAT-positive) neurons in the basal forebrain of 2-month-old AD11 mice.
Increased the number of phosphotau-positive neurons in the entorhinal cortex of 2-month-old AD11 mice at 3 mg/kg/d, with no corresponding increase in phosphotau protein levels via western blot.
Ameliorated the cholinergic deficit in the basal forebrain of 6-month-old AD11 mice.
Increased the number of PS1-, BACE1-, and β-amyloid-positive clusters in the hippocampus of 6-month-old AD11 mice at 3 mg/kg/d.
Increased the number of PS1-positive clusters in the hippocampus of 6-month-old AD11 mice at 6 mg/kg/d.
Prevented the object discrimination deficit at the 1-hour choice phase of the object recognition test in 6-month-old AD11 mice at 6 mg/kg/d, with no effect at the 24-hour phase.
Caused death in two mice in the 6 mg/kg/d oral treatment group (2 to 6 months of age).
Showed no increased lethality in 2-month-old mice and no body weight differences in mice that completed treatment.
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Animal Model:Wistar rats (male, 200-250 g)[5]
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Dosage:1.5, 3 mg/kg
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Administration:p.o.; single dose; once daily for 6 consecutive days followed by a 3 mg/kg oral challenge dose
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Result:Significantly increased extracellular ACh concentrations in the prefrontal cortex after a single oral dose of 3 mg/kg.
Did not significantly increase extracellular ACh concentrations after a single oral dose of 1.5 mg/kg.
Repeated oral treatment with 3 mg/kg once daily for 6 days significantly increased basal extracellular ACh concentrations in the prefrontal cortex.
A 3 mg/kg oral challenge dose after repeated treatment further increased ACh concentrations, reaching 332% above baseline at 200 minutes and remaining significantly elevated for 4 hours.
Did not affect extracellular concentrations of serotonin (5-HT), noradrenaline (NA), dopamine (DA), DOPAC, or HVA after acute administration at 1.5 or 3 mg/kg, repeated treatment at 3 mg/kg, or the 3 mg/kg challenge dose.
At 3 mg/kg, reversed scopolamine-induced deficits in habituation and non-spatial working memory, restoring reduced exploratory activity during trial T2 compared with T1 and preference for the novel object over the familiar object.
Did not significantly reverse scopolamine-induced habituation or object-recognition deficits at 1.5 mg/kg.
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Animal Model:Wistar rats (male)[5]
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Dosage:1.5 mg/kg
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Administration:p.o.; single dose
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Result:Inhibited brain acetylcholinesterase (AChE) with an ED50 of 1.5 mg/kg p.o.
Was almost inactive in inhibiting heart AChE.
Produced significant brain AChE inhibitory activity for up to 16 hours, with peak inhibition of 34% at a single oral dose (one-fifth of its LD50).
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Animal Model:Wistar rats (male, 200-250 g)[5]
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Dosage:1, 10 μM
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Administration:Local retrodialysis via a prefrontal-cortex microdialysis probe; 20-minute perfusion
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Result:Significantly increased extracellular acetylcholine (ACh) concentrations in the prefrontal cortex at 10 μM.
The ACh increase peaked 40 minutes after treatment, reaching 11,061% above baseline, and remained significantly elevated for approximately 120 minutes.
Did not produce a significant increase in extracellular ACh concentrations at 1 μM.
Chemical Information
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CAS. Nr. 457075-21-7
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Molecular Weight 381.47
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Formel C22H27N3O3
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SMILES
C[C@]12C3=CC(OC(NC4=C(C=CC=C4)CC)=O)=CC=C3N([C@@]1([H])ON(CC2)C)C
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Synonyms
CHF 2819 free base
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
Reinheit & Dokumentation
Verweise
[1]. Bartolucci C, et al. Structural determinants of Torpedo californica acetylcholinesterase inhibition by the novel and orally active carbamate based anti-alzheimer drug ganstigmine (CHF-2819). Journal of medicinal chemistry. 2006 Aug 24;49(17):5051-8. [Content Brief]
[2]. Yu QS, et al. Anticholinesterase activity of compounds related to geneserine tautomers. N-Oxides and 1,2-oxazines. Journal of medicinal chemistry. 2002 Aug 15;45(17):3684-91. [Content Brief]
[3]. Windisch M et al. The protective effect of ganstigmine against amyloid beta 25-35 neurotoxicity on chicken cortical neurons is independent from the cholinesterase inhibition. Neurosci Lett. 2003 May 8;341(3):181-4. [Content Brief]
[4]. Capsoni S et al. Ganstigmine and donepezil improve neurodegeneration in AD11 antinerve growth factor transgenic mice. Am J Alzheimers Dis Other Demen. 2004 May-Jun;19(3):153-60. [Content Brief]
[5]. Trabace L et al. Neurochemical and neurobehavioral effects of ganstigmine (CHF2819), a novel acetylcholinesterase inhibitor, in rat prefrontal cortex: an in vivo study. Pharmacol Res. 2007 Oct;56(4):288-94. [Content Brief]
Calculators
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