A-582941
A-582941 is a selective, orally active, blood-brain barrier-permeable α7 nAChR agonist, with Ki values of 10.8 nM and 17 nM in rat brain and human frontal cortex, respectively. A-582941 exhibits agonistic activity at 5-HT3 receptors, with a Ki of 150 nM. A-582941 triggers phosphorylation of ERK1/2 and CREB, inhibits GSK-3β via Ser-9 phosphorylation, increases acetylcholine release, induces the expression of Arc and c-Fos, activates brain regions associated with working memory and attention, and reduces cell death caused by nerve growth factor (NGF) deprivation. A-582941 is applicable for the research of Alzheimer's disease and schizophrenia.
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- CAS No.: 848591-89-9
- Formule: C17H20N4
- Masse moléculaire:280.38
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
- Pureté et documentation
- Références
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Activité biologique
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5-HT3 Receptor 150 nM (Ki) |
A-582941 binds with high affinity to α7 nAChRs in rat brain (Ki = 10.8 nM) and human frontal cortex (Ki = 17 nM) membranes, with slightly lower affinity for antagonist-labeled α7 nAChRs (Ki = 88 nM) in rat brain[1].
A-582941 acts as a partial agonist at recombinant human α7 nAChRs in Xenopus oocytes, with an EC50 of 4260 nM and 52% efficacy relative to acetylcholine[1].
A-582941 acts as a partial agonist at recombinant rat α7 nAChRs in Xenopus oocytes, with an EC50 of 2450 nM and 60% efficacy relative to acetylcholine[1].
A-582941 (3 μM PNU-120596 pre-incubated prior to treatment) exhibits increased potency (EC50 = 580 nM) and efficacy (207% relative to acetylcholine) at recombinant human α7 nAChRs in Xenopus oocytes[1].
A-582941 increases ERK1/2 phosphorylation in α7 nAChR-expressing PC12 cells with an EC50 of 95 nM, an effect mediated by α7 nAChRs[1].
A-582941 (0.1-100 μM) protects PC12 cells from NGF withdrawal-induced cell death[1].
A-582941 (100 nM-10,000 nM; 9 days) does not induce proliferation in cultured human keratinocytes[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Cultured human keratinocytes
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Concentration:100 nM, 10,000 nM
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Incubation Time:9 days, with medium refreshed every 3-4 days
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Result:Produced no detectable proliferation under conditions where serum/growth factor supplements evoked significant proliferative events.
| Species | Dose | Route | T1/2 | Vss | CLplasma | Cmax | Bioavailability |
|---|---|---|---|---|---|---|---|
| Mice[1] | 1.0 μmol/Kg | i.v. | 1.4 h | 11.4 L/kg | 7.9 L/h/kg | / | / |
| Mice[1] | 1.0 μmol/Kg | p.o. | / | / | / | 18 ng/mL | ~100 % |
| Rat[1] | 6.2 μmol/Kg | i.v. | 1.5 h | 9.2 L/kg | 4.7 L/h/kg | / | / |
| Rat[1] | 6.2 μmol/Kg | p.o. | / | / | / | 114 ng/mL | 90 % |
| Dog[1] | 0.5 μmol/Kg | i.v. | 1.4 h | 7.9 L/kg | 5.3 L/h/kg | / | / |
| Dog[1] | 3.0 μmol/Kg | p.o. | / | / | / | 79 ng/mL | 22 % |
| Monkey[1] | 0.5 μmol/Kg | i.v. | 2.0 h | 3.9 L/kg | 1.6 L/h/kg | / | / |
| Monkey[1] | 3.0 μmol/Kg | p.o. | / | / | / | 39 ng/mL | 50 % |
A-582941 (0.01-1.00 μmol/kg; i.p.) improves memory consolidation in mice, with full efficacy achieved at 0.1 μmol/kg (i.p.)[1].
A-582941 (0.1-1.0 μmol/kg; i.p.) dose-dependently increases Ser-9 GSK-3β phosphorylation in the mouse cingulate cortex[1].
A-582941 (0.1-1.0 μmol/kg; i.p.) improves short-term recognition memory in rats, with full efficacy achieved at 0.1 μmol/kg (i.p.)[1].
A-582941 (3 μmol/kg; i.p.; once daily; 3 consecutive days) moderately increases medial prefrontal cortex acetylcholine release in freely moving rats[1].
A-582941 (1.8 μmol/kg/day; s.c.; continuous infusion; 7 days) maintains efficacy in improving rat short-term recognition memory[1].
A-582941 (0.003-0.100 μmol/kg; i.m.) improves working memory in young Rhesus monkeys, with full efficacy achieved at 0.01 μmol/kg (i.m.)[1].
A-582941 (10 μmol/kg; i.p.) reverses MLA (HY-N2332)-induced sensory gating deficit in rats[1].
A-582941 (3-10 μmol/kg; i.p.) improves genetic sensory gating deficit in DBA/2J mice, with efficacy retained after 5 consecutive days of 3 μmol/kg (i.p.) dosing[1].
A-582941 (0.1-1.0 μmol/kg; s.c.) modestly improves response inhibition/impulsivity in spontaneously hypertensive rat pups[1].
A-582941 (0.1-10 mg/kg; s.c.; single dose) induces dose-dependent increases in Arc and c-Fos mRNA and protein expression in limbic forebrain regions of juvenile male Wistar rats, with maximal effects at 10 mg/kg and greater responsiveness observed in juvenile compared to adult rats[2].
A-582941 (0.1-10 mg/kg; s.c.; single dose) increases Arc and c-Fos immunoreactive cell counts in limbic forebrain regions of adult male Wistar rats at 10 mg/kg, but does not induce measurable increases in Arc or c-Fos mRNA expression in any examined region[2].
A-582941 (1.14-38 μg/kg; i.m.; single dose) significantly improves delayed matching-to-sample task accuracy in young adult Rhesus monkeys, with a 22.2% increase in long delay trial accuracy (twice the magnitude of improvement in short delay trials) that is not sustained 24 hours after dosing[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:unspecified strain[1]
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Dosage:1.8 μmol/kg/day
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Administration:s.c.; continuous infusion; 7 days
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Result:Maintained efficacy in the social recognition test, as reflected by a reduced ratio of investigative behavior during the second session (T2) compared to the first session (T1).
Reached a mean steady-state plasma concentration of 3.1 ± 0.3 ng/mL (11 nM).
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Animal Model:DBA/2J[1]
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Dosage:3 μmol/kg (acute; 5-day repeated dosing); 10 μmol/kg (acute)
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Administration:i.p.; acute; once daily; 5 consecutive days
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Result:Significantly improved sensory gating in acutely treated mice.
Retained efficacy after 5 consecutive days of dosing with 3 μmol/kg (i.p.).
Reached an average plasma concentration of 44 ng/mL (157 nM) after 5 days of repeated dosing.
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Animal Model:Wistar rats (adult, male, approximately 55 days, 210-230 g)[2]
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Dosage:0.1, 0.3, 1, 3 and 10 mg/kg
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Administration:s.c.; single dose
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Result:Did not induce significant increases in Arc or c-Fos mRNA expression in any brain region examined (mPFC, VO/LO cortex, hippocampus).
Increased Arc immunoreactive cell counts at 10 mg/kg in the mPFC (262% increase vs controls), VO/LO cortex (233% increase vs controls), ACCshell (851% increase vs controls), and dmSTR (419% increase vs controls); no significant effect was seen in the ACCcore or dlSTR.
Increased c-Fos immunoreactive cell counts at 10 mg/kg in the mPFC (97% increase vs controls), VO/LO cortex (115% increase vs controls), and ACCshell (169% increase vs controls); no significant effect was seen in the ACCcore, dmSTR, or dlSTR.
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Animal Model:Macaca mulatta (male, 9-18 years old, 7.2-11.8 kg)[3]
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Dosage:1.14 μg/kg; 3.8 μg/kg; 11.4 μg/kg; 38 μg/kg
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Administration:i.m.; single dose
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Result:Significantly improved delayed matching-to-sample (DMTS) task accuracies relative to vehicle controls.
Produced a significant increase in short delay trial accuracy at 11.4 μg/kg dose.
Produced significant increases in long delay trial accuracy at 1.14 μg/kg, 3.8 μg/kg, and 11.4 μg/kg doses.
Increased long delay trial accuracy by 22.2% above control, approximately twice the 11.3% increase observed in short delay trials.
Showed a non-significant trend toward improved accuracy at 38 μg/kg dose.
Produced no statistically significant improvement in task accuracies during sessions initiated 24 hours after dosing, despite mean long delay accuracies remaining above vehicle levels.
Produced no significant effect on sample or choice task latencies.
Chemical Information
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CAS No. 848591-89-9
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Masse moléculaire 280.38
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Formule C17H20N4
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SMILES
N=1N=C(C=CC1C=2C=CC=CC2)N3CC4CN(C)CC4C3
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
[1]. Tietje KR, et al. Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties. CNS Neurosci Ther. 2008;14(1):65-82. [Content Brief]
[2]. Thomsen MS, et al. The selective alpha7 nicotinic acetylcholine receptor agonist A-582941 activates immediate early genes in limbic regions of the forebrain: Differential effects in the juvenile and adult rat. Neuroscience. 2008;154(2):741-753. [Content Brief]
[3]. Buccafusco JJ, et al. Profile of nicotinic acetylcholine receptor agonists ABT-594 and A-582941, with differential subtype selectivity, on delayed matching accuracy by young monkeys. Biochem Pharmacol. 2007;74(8):1202-1211. [Content Brief]
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