| Size | Price | Stock | Qty |
|---|---|---|---|
| 500mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
The primary target is the orphan nuclear receptor Nurr1 (NR4A2), specifically its ligand‑binding domain (LBD). Amodiaquine binds to Nurr1‑LBD with a Kᵢ of 246 nM (competition against [³H]‑chloroquine). The dissociation constant (Kd) for chloroquine binding to Nurr1‑LBD was 0.27 µM, and AQ competed for this binding with a Kᵢ of 246 nM. EC₅₀ for Nurr1 LBD‑dependent transcriptional activation was approximately 20 µM. No IC₅₀ values were reported. [1]
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| ln Vitro |
The expression of LPS-induced pro-inflammatory cytokines (IL-1β, interleukin 6, TNF-α, and iNOS) is inhibited in a dose-regulated manner by amodiaquine dihydrochloride (10–20 μM; 4 hours) administration [1]. μM; 24 hr) markedly reduced the amount of neurotoxic (6-OHDA) that caused cell death in primary dopamine cells, as indicated by the quantity of TH+ neurons and dopamine chow. Amodiaquine was also found to have neuroprotective properties in tea PC12 cells using the use of RT-PCR.
Amodiaquine activated Nurr1‑dependent transcriptional activity in a dose‑dependent manner, showing approximately 3‑fold activation of full‑length Nurr1 reporter and up to 15‑fold activation of Nurr1 LBD‑based reporter, with an EC₅₀ of ~20 µM. It enhanced the interaction between Nurr1 and transcriptional coactivators SRC‑1 and SRC‑3, as shown by co‑immunoprecipitation. Amodiaquine promoted the generation of TH⁺ neurons from rat neural stem cells during in vitro differentiation and increased mRNA expression of mDA‑specific genes including TH, DAT, VMAT, and AADC. It showed neuroprotective effects against 6‑OHDA‑induced cell death in primary rat mesencephalic DA neurons (increasing TH⁺ neuron survival and DA uptake) and in PC12 cells (MTT assay). In primary rat microglia, Amodiaquine (10‑20 µM) suppressed LPS‑induced expression of proinflammatory cytokines IL‑1β, IL‑6, TNF‑α, and iNOS in a dose‑dependent manner. Nurr1‑specific siRNA knocked down Nurr1 expression and reduced Amodiaquine‑induced luciferase activation by more than 80%, confirming the effect is Nurr1‑dependent. ChIP assay showed that Amodiaquine enhanced Nurr1 recruitment to the TH promoter at NL1 and NL3 sites. [1] |
| ln Vivo |
Amodiaquine (40 mg/kg; intraperitoneal; daily; for 3 days; stable ICR tumors) treatment decreased the peritumor activation of stellate stellate cells and tiny stellate cells/macrophages. Amodiaquine also ameliorates motor impairment in mice and suppresses ICH-induced mRNA expression of IL-1β, CCL2, and CXCL2 [2].
In a 6‑OHDA‑lesioned rat model of Parkinson's disease, Amodiaquine (10 mg/kg, i.p., daily for 4 weeks) significantly improved behavioral deficits. In amphetamine‑induced rotation tests, AQ‑treated rats showed ~3.5 rotations/min compared to ~10 rotations/min in saline‑treated controls at 4 weeks post‑lesion. In the stepping test, AQ‑treated rats showed ~70% of normal stepping ability, whereas saline‑treated rats showed ~30%. AQ treatment significantly increased the number of TH⁺ neurons in the lesioned substantia nigra to ~60% of the intact side at 6 weeks post‑lesion, compared to <20% in saline‑treated animals. TH⁺ cells co‑expressed FoxA2 and AADC. Amodiaquine suppressed microglial activation in the ipsilateral substantia nigra and striatum, as shown by reduced Iba‑1⁺ microglia counts. No dyskinesia‑like abnormal involuntary movements were observed in AQ‑treated rats, in contrast to L‑DOPA‑treated controls which showed significant AIMs. [1] |
| Enzyme Assay |
Surface plasmon resonance (SPR) using Biacore S51 showed that Amodiaquine specifically bound to Nurr1‑LBD in a dose‑dependent manner, but not to RXR‑LBD. The purified Nurr1‑LBD polypeptide (amino acids 328‑598) was used.
Fluorescence quenching analysis: Nurr1‑LBD displayed maximal fluorescence at 336 nm. Incubation with increasing amounts of Amodiaquine gradually decreased fluorescence intensity, indicating binding. RXR‑LBD showed no quenching with AQ. Radioligand binding assay using [³H]‑chloroquine: [³H]‑CQ showed saturable binding to Nurr1‑LBD with a Kd of 0.27 µM and Bmax of 13.9 µM. Competition binding assay showed that unlabeled Amodiaquine competed for [³H]‑CQ binding with a Ki of 246 nM. NMR titration experiments using ²D ¹H‑¹⁵N TROSY‑HSQC spectra of uniformly ¹⁵N‑labeled Nurr1‑LBD: addition of Amodiaquine caused concentration‑dependent chemical shift perturbations in residues mainly located in helix α2 (H402, I403, Q404, Q405, D408, L409) and α11 (V468, Y575, D580). [1] |
| Cell Assay |
RT-PCR[1]
Cell Types: primary microglia Tested Concentrations: 10μM, 15μM, 20μM Incubation Duration: 4 hrs (hours) Experimental Results: Inhibition of LPS-induced pro-inflammatory cytokines (IL-1β, interleukin-6, TNF - 1]. α and iNOS) in a dose-dependent manner. Cell‑based reporter assays: Human neuroblastoma SK‑N‑BE(2)C cells were transfected with p4xNL3‑Luc (four copies of NBRE‑like motif) and pCMV‑Nurr1 (full‑length Nurr1), or pGAL‑Nurr(LBD) and pGAL‑Nurr(DBD) constructs, treated with compounds for 24 h, and luciferase activity measured. siRNA knockdown: Cells were treated with Nurr1‑specific siRNA or scrambled RNA, and Nurr1 protein expression and AQ‑induced luciferase activation were assessed. Nurr1 siRNA reduced AQ‑induced activation by >80%. Co‑immunoprecipitation: Nurr1 interaction with SRC‑1 and SRC‑3 in SK‑N‑BE(2)C cells was examined with or without Amodiaquine treatment; AQ enhanced these interactions. Neural stem cell differentiation: Neural progenitors from E14.5 rat cortex were differentiated by bFGF withdrawal, treated with AQ for 2 h during differentiation, and immunocytochemistry for TH and qRT‑PCR for mDA genes (TH, DAT, VMAT, AADC) performed at 3 and 9 days. Neuroprotection assays: Primary rat mesencephalic DA neurons and PC12 cells were treated with 6‑OHDA (20 µM for 24 h) in the presence or absence of Amodiaquine (5 µM for primary neurons; various concentrations for PC12). TH⁺ neuron counting, [³H]DA uptake, and MTT reduction assay were used to measure cell survival. Microglial assay: Primary microglia from P1 rat brains were treated with LPS (10 ng/mL, 4‑8 h) with or without Amodiaquine (10‑20 µM), and mRNA levels of IL‑1β, IL‑6, TNF‑α, and iNOS were measured by qRT‑PCR. ChIP assay: Rat PC12 cells treated with Amodiaquine (20 µM) or chloroquine (70 µM) were used for chromatin immunoprecipitation with anti‑Nurr1 antibody to assess Nurr1 recruitment to TH promoter NL1 and NL3 sites. [1] |
| Animal Protocol |
Animal/Disease Models: Male ICR mice (8-10 weeks old) induced intracerebral hemorrhage (ICH) [2]
Doses: 40 mg/kg Route of Administration: intraperitoneal (ip) injection; daily; lasted for 3 days Experimental Results: Microglia around the hematoma / diminished activation of macrophages and astrocytes. Animal experiments were performed in accordance with institutional guidelines. Adult Sprague‑Dawley rats were used. The 6‑OHDA lesion model: rats received unilateral stereotaxic injection of 6‑OHDA (8 µg in 4 µL saline with 0.02% ascorbic acid) into the medial forebrain bundle. After 2 weeks, rats with >6 rotations/min in amphetamine‑induced rotation test were selected. Amodiaquine was administered intraperitoneally at 10 mg/kg daily for 4 weeks. L‑DOPA (6 mg/kg plus 15 mg/kg benserazide) was used as a positive control for efficacy and dyskinesia assessment. Saline was used as vehicle control. Behavioral tests: Amphetamine‑induced rotation test (2.5 mg/kg amphetamine, i.p.) was performed at 2, 4, and 6 weeks post‑lesion. Stepping test was performed at 4 weeks. Abnormal involuntary movements (AIMs) were scored every 30 min for 3 h after drug administration. Histological analysis: At 6 weeks post‑lesion, brains were processed for immunohistochemistry. TH⁺ neurons in substantia nigra were stereologically counted in a blind manner. Microglial activation was assessed by Iba‑1 immunohistochemistry in SN and striatum. [1] |
| Toxicity/Toxicokinetics |
Amodiaquine hydrochloride (CAS# 69‑44‑3) is an antimalarial drug that also acts as a potent inhibitor of histamine N‑methyltransferase (HNMT), the enzyme responsible for intracellular histamine inactivation. This study reveals that Amodiaquine binds to HNMT in a unique dual‑site manner: one molecule occupies the active site (competitive inhibition) and a second binds to an outer‑surface pocket (uncompetitive inhibition), resulting in a mixed inhibition mode. This dual binding may account for its exceptionally low Ki (18.6 nM in this study, or 7.5 nM in the literature) compared to other HNMT inhibitors. The structure shows that the quinoline ring is sandwiched between aromatic residues, and the alkylamino tail interacts with Glu246 and Cys196. The outer‑surface pocket binding has been exploited for affinity purification of HNMT using amodiaquine‑Sepharose columns. The study suggests that the interaction between amodiaquine and Gln94 (a residue normally involved in AdoMet/AdoHcy binding) may affect cofactor binding. No in vivo, ADME, or toxicity data are presented in this study. The compound is FDA‑approved for antimalarial use; its HNMT inhibition represents an off‑target activity. [5]
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| References |
[1]. Chun-Hyung Kim, et al. Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson's disease. Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):8756-61.
[2]. Keita Kinoshita, et al. A Nurr1 agonist amodiaquine attenuates inflammatory events and neurological deficits in a mouse model of intracerebral hemorrhage. J Neuroimmunol. 2019 May 15;330:48-54. [3]. Akira Yokoyama, et al. Effect of amodiaquine, a histamine N-methyltransferase inhibitor, on, Propionibacterium acnes and lipopolysaccharide-induced hepatitis in mice. Eur J Pharmacol. 2007 Mar 8;558(1-3):179-84. [4]. M T HOEKENGA. The treatment of acute malaria with single oral doses of amodiaquin, chloroquine, hydroxychloroquine and pyrimethamine. Am J Trop Med Hyg. 1954 Sep;3(5):833-8. [5]. John R Horton, et al. Structural basis for inhibition of histamine N-methyltransferase by diverse drugs. J Mol Biol. 2005 Oct 21;353(2):334-344. |
| Additional Infomation |
Amodiaquine hydrochloride is the hydrochloride salt of amodiaquine, an orally effective 4-aminoquinoline derivative with antimalarial and anti-inflammatory properties. Amodiaquine has a structure and activity similar to chloroquine and is effective against some chloroquine-resistant strains, particularly against Plasmodium falciparum (the most deadly malaria parasite). Although its mechanism of action against malaria parasites is not fully understood, like other quinoline derivatives, amodiaquine may inhibit the activity of heme polymerase in vivo. This leads to the accumulation of free heme, which is toxic to parasites.
Amodiaquine hydrochloride (CAS# 69‑44‑3) is an antimalarial drug identified in this study as a Nurr1 agonist. It shares a 4‑amino‑7‑chloroquinoline scaffold with chloroquine and glafenine. The compound was found to bind directly to Nurr1‑LBD, a nuclear receptor previously thought to be ligand‑independent due to the absence of a classical binding pocket. The mechanism involves physical binding to Nurr1‑LBD, enhancing recruitment of SRC‑1/SRC‑3 coactivators, leading to increased transcriptional activation of mDA neuron genes and transrepression of proinflammatory genes in microglia. In a 6‑OHDA rat model of Parkinson's disease, Amodiaquine improved motor deficits, protected DA neurons, and suppressed neuroinflammation without dyskinesia side effects. The study provides proof‑of‑concept that Nurr1 is a druggable target for PD. The compound is FDA‑approved for antimalarial use, but its use for PD is investigational. No FDA warnings specific to this indication are mentioned. The study was supported by NIH grants and the Michael J. Fox Foundation. [1] |
| Molecular Formula |
C20H24CL3N3O
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|---|---|
| Molecular Weight |
428.7831
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| Exact Mass |
391.121
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| CAS # |
69-44-3
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| Related CAS # |
Amodiaquine dihydrochloride dihydrate;6398-98-7;Amodiaquine;86-42-0
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| PubChem CID |
6246
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| Appearance |
Light yellow to yellow solid powder
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| Boiling Point |
478ºC at 760 mmHg
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| LogP |
6.054
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
27
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| Complexity |
406
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCN(CC)CC1=C(C=CC(=C1)NC2=C3C=CC(=CC3=NC=C2)Cl)O.O.O.Cl.Cl
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| InChi Key |
ROEBJVHPINPMKL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H22ClN3O.2ClH/c1-3-24(4-2)13-14-11-16(6-8-20(14)25)23-18-9-10-22-19-12-15(21)5-7-17(18)19/h5-12,25H,3-4,13H2,1-2H3,(H,22,23)2*1H
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| Chemical Name |
4-[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol
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| Synonyms |
Amodiaquin dihydrochloride dihydrate
Amodiaquin dihydrochloride Amodiaquine hydrochloride dihydrate
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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 (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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) |
DMSO : ~125 mg/mL (~291.52 mM)
H2O : ~50 mg/mL (~116.61 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.85 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.85 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3322 mL | 11.6610 mL | 23.3220 mL | |
| 5 mM | 0.4664 mL | 2.3322 mL | 4.6644 mL | |
| 10 mM | 0.2332 mL | 1.1661 mL | 2.3322 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00894660 | COMPLETED | Drug: Amodiaquine (Test) Drug: Amodiaquine (Comparator) |
Falciparum Malaria | Pfizer | 2009-06 | Phase 1 |
| NCT00238017 | UNKNOWN STATUS | Drug: amodiaquine-artesunate versus amodiaquine | Malaria | Charite University, Berlin, Germany | 2005-10 | Phase 4 |
| NCT00859807 | COMPLETED | Drug: Flavoquine®, Camoquin® Suspension | Falciparum Malaria | Pfizer | 2009-05 | Phase 4 |
| NCT01023399 | COMPLETED | Drug: Artesunate + Amodiaquine | Malaria | Sanofi | 2009-11 | Phase 4 |
| NCT04080895 | RECRUITING | Drug: Artemether-lumefantrine Drug: Amodiaquine Drug: Artemether-lumefantrine Drug: Artemether-lumefantrine + Amodiaquine |
Drug Combination Healthy Pharmacokinetic |
University of Oxford | 2022-11-01 | Phase 1 |
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