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| Targets |
ABT-418 targets neuronal nicotinic acetylcholine receptors (nAChRs), displaying the highest potency at alpha4beta2 and alpha2beta2 subtypes with EC50 values of approximately 6 and 11 uM, respectively. It appears to function as a relatively broad-spectrum activator of neuronal nicotinic receptors with little cross-reactivity to the mammalian muscle receptor subtype. Like (-)-nicotine, it acts as a cholinergic channel activator, but with a distinct pharmacological profile.
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| ln Vitro |
In vitro, ABT-418 activates ganglionic nicotinic acetylcholine receptors in PC12 cells and other neuronal preparations. It has been used as a nicotinic acetylcholine receptor agonist to study its effects on spatial memory in ADHD rat models. The compound shows neuronal nAChR activation with little cross-reactivity to the muscle receptor subtype. In addition to activating neuronal receptors, ABT-418 exhibits complex properties including the inhibition of ACh responses at higher concentrations.
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| ln Vivo |
Rats exposed to ABT-418 hydrochloride (125.66 μg/kg; intraperitoneal) spend a notably longer amount of time in the raised plus maze's open arms [1]. ABT-418 (125.66 μg/kg; intraperitoneal injection) administered acutely also lessens the anxiolytic effects of stopping long-term (-)-nicotine therapy [1]. Animal models of ADHD can benefit from ABT-418 hydrochloride (0.6 mg/kg; intraperitoneal injection; daily; for two weeks) in terms of improved spatial memory [2]. The expression of the hippocampus α4 subunit and cortical α4 and β2 nAChR subunits is markedly increased by ABT-418 hydrochloride [2].
In vivo, ABT-418 induces anxiolytic-like effects in mice in the elevated plus maze. In rats, ABT-418 (0.62 umol/kg i.p.) significantly increases time spent in the open arms of the elevated plus maze, with effects persisting up to 60 minutes after injection. The anxiolytic effect was blocked by mecamylamine (15 umol/kg), a centrally acting nAChR channel blocker. ABT-418 was 6-fold more potent than diazepam and 1.6-fold more potent than ondansetron. The anxiolytic-like effect was observed after oral administration (10-30 umol/kg) in rats and at slightly higher doses in 20-month-old rats (1.9 umol/kg i.p.). Like (-)-nicotine, ABT-418 was effective at 4 and 13 umol/kg/day via subcutaneous minipumps to induce anxiolytic effects after 14-day treatment. Acute ABT-418 (0.62 umol/kg i.p.) attenuated the anxiogenic-like effect from withdrawal of chronic (-)-nicotine treatment. In primates, ABT-418 reduces distractibility. In Alzheimer's disease patients, it improves cognition. Major metabolites (S)-1-methyl-5-(3-methyl-5-isoxazolyl)-2-pyrrolidinone, cis-ABT-418 N-oxide, and trans-ABT-418 N-oxide were inactive in the plus maze test in mice up to 6.2 umol/kg. |
| Enzyme Assay |
For nAChR binding assays: Incubate rat brain membranes (cortex or hippocampus) with 3H-cytisine (1-2 nM) or 3H-epibatidine (0.1 nM) for displacement assays. Add varying concentrations of ABT-418 (1 nM to 100 uM) in binding buffer (50 mM Tris-HCl, pH 7.4, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2). Incubate at 25degC for 60-90 minutes. Filter through GF/B filters presoaked in 0.3% polyethylenimine. Count radioactivity by liquid scintillation. Calculate Ki and IC50 values. For functional assays (calcium influx): Express human nAChR subtypes (alpha4beta2, alpha2beta2) in Xenopus oocytes or HEK293 cells. Treat with ABT-418 (0.1-100 uM) and measure whole-cell currents by patch-clamp or calcium flux using fluorescent dyes (Fluo-4). Calculate EC50 values (approximately 6 uM for alpha4beta2, 11 uM for alpha2beta2).
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| Cell Assay |
For cell-based assays using PC12 cells: Culture PC12 cells in DMEM with 10% FBS and 50 ng/mL NGF to induce neuronal differentiation. Treat cells with ABT-418 (1-100 uM) for 30-60 minutes. Measure intracellular calcium using Fluo-4 or Fura-2. Alternatively, measure dopamine release by HPLC-ECD.
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| Animal Protocol |
Animal/Disease Models: Male SHR (4-5 weeks old), attention deficit hyperactivity disorder (ADHD) model [2]
Doses: 0.6 mg/kg Route of Administration: intraperitoneal (ip) injection; one time/day; two-week effect: spatial memory is effectively improved. For in vivo behavioral assays in mice/rats (elevated plus maze): Administer ABT-418 intraperitoneally (0.31-1.25 umol/kg in mice, 0.31-1.24 umol/kg in rats) or orally (10-30 umol/kg in rats) in saline. Fifteen minutes (i.p.) or 60 minutes (oral) after injection, place animals in the elevated plus maze (two open arms, two closed arms) for 5 minutes. Record time spent in open arms, number of open arm entries, and total arm entries. Anxiolytic effect is indicated by increased open arm time and entries. Diazepam (1-2 mg/kg) can be used as a positive control. For chronic administration via minipumps: Implant ALZET minipumps subcutaneously in mice or rats to deliver ABT-418 at 4 or 13 umol/kg/day for 14 days. Perform behavioral tests during or after treatment. For nicotine withdrawal studies: Treat mice with chronic (-)-nicotine via minipumps (24 mg/kg/day) for 14 days. Withdraw nicotine for 24 hours. Administer ABT-418 (0.62 umol/kg i.p.) 15 minutes before behavioral testing in the elevated plus maze. |
| ADME/Pharmacokinetics |
The compound is expected to have moderate pharmacokinetics typical of small molecules that cross the blood-brain barrier. It is soluble in water (up to 15 mg/mL) and DMSO. Stock solutions in distilled water can be stored at -20degC for up to 3 months. ABT-418 hydrochloride is stable for 1 year from date of purchase as supplied. As a nAChR agonist that crosses the blood-brain barrier, it is expected to have a short to moderate half-life (similar to nicotine, approximately 1-2 hours in rodents).
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| Toxicity/Toxicokinetics |
The compound was generally well tolerated in clinical studies in Alzheimer's patients. In preclinical studies, ABT-418 did not affect body temperature and had minimal effects on locomotion at anxiolytic doses. Major metabolites were inactive in behavioral tests. The compound has a favorable safety profile in animal studies. For human use, mild adverse effects were observed in clinical trials, including gastrointestinal discomfort and mild sedation. However, the compound did not advance to regulatory approval.
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| References | |
| Additional Infomation |
ABT-418 hydrochloride is a research compound that was studied clinically but did not receive regulatory approval. It has been investigated in phase II clinical trials for Alzheimer's disease, showing cognition-enhancing effects in patients. It was also studied for attention deficit hyperactivity disorder (ADHD). The compound is a neuronal nicotinic acetylcholine receptor agonist, which was a novel mechanism for cognition enhancement at the time of its development. It is no longer commercially available as a therapeutic and is now used as a research tool to study nAChR function. The compound is for research use only. It should be stored as a powder at -20degC in a dry, dark environment. It is soluble in water (15 mg/mL) and DMSO. No FDA or EMA approval exists.
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| Molecular Formula |
C₉H₁₅CLN₂O
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| Molecular Weight |
202.68
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| Exact Mass |
202.087
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| CAS # |
147388-83-8
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| PubChem CID |
10375597
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| Appearance |
Light brown to brown solid powder
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| Boiling Point |
249.2ºC at 760 mmHg
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| Flash Point |
104.5ºC
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| Vapour Pressure |
0.0232mmHg at 25°C
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| LogP |
2.489
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
13
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| Complexity |
163
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=NOC(=C1)[C@@H]2CCCN2C.Cl
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| InChi Key |
VOXHERKWAIEJQF-QRPNPIFTSA-N
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| InChi Code |
InChI=1S/C9H14N2O.ClH/c1-7-6-9(12-10-7)8-4-3-5-11(8)2;/h6,8H,3-5H2,1-2H3;1H/t8-;/m0./s1
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| Chemical Name |
3-methyl-5-[(2S)-1-methylpyrrolidin-2-yl]-1,2-oxazole;hydrochloride
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| Synonyms |
ABT418 HCl; ABT 418 HCl
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
H2O : ~11.9 mg/mL (~58.71 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 100 mg/mL (493.39 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.9339 mL | 24.6694 mL | 49.3389 mL | |
| 5 mM | 0.9868 mL | 4.9339 mL | 9.8678 mL | |
| 10 mM | 0.4934 mL | 2.4669 mL | 4.9339 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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