| Size | Price | Stock | Qty |
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| 100mg |
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| 250mg |
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Purity: ≥98%
Doxapram hydrochloride (AHR619) is a respiratory stimulant that can also inhibit TASK-1, TASK-3, TASK-1/TASK-3 heterodimeric channel function with EC50 of 410 nM, 37 μM, 9 μM, respectively. Doxapram preferentially stimulated the release of dopamine. It was also seen to directly inhibit Ca(2+)-independent K+ currents. Doxapram was a more potent inhibitor of the Ca(2+)-activated K+ currents recorded under control conditions. Doxapram (at 15-150 μM) also evoked 3H overflow in a concentration dependent manner, and doxapram-evoked release was inhibited by the Ca2+ channel blocker nifedipine (5 μM). The effects of doxapram on type I cells show similarities to those of the physiological stimuli of the carotid body, suggesting that doxapram may share a similar mechanism of action in stimulating the intact organ.
| Targets |
TASK-1 (KCNK3) potassium channel (EC50 = 410 nM)
TASK-3 (KCNK9) potassium channel (EC50 = 37 μM) TASK-1/TASK-3 heterodimeric potassium channel (EC50 = 9 μM) TASK-3-1 chimera (carboxy terminus from TASK-1) (EC50 = 800 nM) TASK-1-3 chimera (carboxy terminus from TASK-3) (EC50 = 5 μM) TRESK (K2P) channel (EC50 = 240 μM) TASK-2 (K2P) channel (EC50 = 460 μM) TREK-1 (K2P) channel (EC50 > 1 mM) [1] |
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| ln Vitro |
Doxapram inhibited TASK-1 channel function in a dose-dependent manner with an EC50 of 410 nM; inhibition was slowly reversible (more than 10 minutes). Doxapram inhibited TASK-3 channel function with an EC50 of 37 μM; inhibition reversed more rapidly (approximately 5 minutes). Doxapram inhibited the TASK-1/TASK-3 heterodimeric channel (expressed as a fused single protein to ensure 1:1 stoichiometry) with an EC50 of 9 μM. Doxapram depolarized the resting transmembrane potential (RMP) of oocytes expressing TASK-3 (from -78 ± 6 mV to -51 ± 2 mV at 30 μM) and the TASK-1/TASK-3 heterodimer (from -76 ± 12 mV to -49 ± 10 mV at 10 μM), and this effect was partially reversible upon washout. Doxapram had no effect on the RMP of uninjected oocytes. The extent of inhibition of the TASK-1/TASK-3 heterodimer by 5 μM doxapram was unaffected by extracellular pH (pH 6.5, 7.4, 8.5), by halothane (250 μM, 1 MAC), or by high extracellular potassium (115 mM KCl). Pure doxapram (in the absence of benzyl alcohol) inhibited the TASK-3-1 chimera (1 μM; 69.5% ± 5.1%) and the TASK-1/TASK-3 heterodimer (10 μM; 54.7% ± 5.6%) with potency similar to the benzyl alcohol-containing preparation. Doxapram inhibited the TASK-3-1 chimera (with carboxy terminus from TASK-1) with an EC50 of 800 nM, similar to TASK-1, and inhibited the TASK-1-3 chimera (with carboxy terminus from TASK-3) with an EC50 of 5 μM, intermediate between TASK-1 and TASK-3. Doxapram also inhibited TRESK (EC50 240 μM), TASK-2 (EC50 460 μM), and TREK-1 (EC50 >1 mM) but at significantly larger concentrations. [1]
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| ln Vivo |
Intravenous infusion of doxapram in rats anesthetized with halothane did not change the minimum alveolar concentration (MAC) for halothane. The MAC values were: Stage 1 (baseline) 1.05% ± 0.11%, Stage 2 (repeat) 1.00% ± 0.12%, and Stage 3 (during doxapram infusion) 0.96% ± 0.15% (P = 0.65 by ANOVA). This suggests that doxapram does not affect halothane-induced immobility. [1]
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| Enzyme Assay |
TASK-1, TASK-3, TASK-1/TASK-3 heterodimeric, TASK-1/TASK-3 chimeric, and other K2P channels (TRESK, TASK-2, TREK-1) were expressed in Xenopus oocytes by injection of complementary RNA (cRNA). Channel function was studied using the two-electrode voltage clamp technique. Data were collected during a 1-second pulse to +60 mV from a holding potential. Outward currents were measured. For dose-response experiments, increasing concentrations of doxapram were applied extracellularly, and the steady-state inhibition was recorded. Because of poor washout for TASK-1, no more than one doxapram dose was used per oocyte. For TASK-3 and other channels with easier washout, one or two doses were applied per oocyte. Half-maximal effective concentrations (EC50) were calculated from the dose-response data. The reversibility of inhibition was assessed by measuring current inhibition at steady-state and 5 minutes after doxapram washout. For resting transmembrane potential (RMP) measurements, oocytes were impaled with microelectrodes and the membrane potential was recorded under current-clamp mode before, during, and after doxapram application. For chimera studies, the carboxy terminal domains of TASK-1 and TASK-3 were exchanged. The TASK-3-1 chimera contained amino acids Met-1 through Phe-246 from TASK-3 and amino acids Met-247 through Val-411 from TASK-1. The TASK-1-3 chimera contained amino acids Met-1 through Phe-246 from TASK-1 and amino acids Leu-247 through Iso-396 from TASK-3. The effect of extracellular pH was tested by changing the bath solution to pH 6.5 or pH 8.5. The effect of halothane was tested by applying 250 μM halothane. High extracellular potassium condition was achieved with 115 mM KCl. [1]
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| Cell Assay |
Xenopus oocytes were injected with complementary RNA (cRNA) encoding TASK-1, TASK-3, TASK-1/TASK-3 heterodimer (fused as a single protein), TASK-1/TASK-3 chimeras, TRESK, TASK-2, or TREK-1 channels. Injected oocytes were cultured and then used for two-electrode voltage clamp recordings. For resting transmembrane potential (RMP) measurements, oocytes expressing TASK-3, TASK-1/TASK-3 heterodimer, or chimeric channels were impaled with microelectrodes, and the RMP was recorded under current-clamp mode at baseline, during doxapram application, and after 5 minutes of washout. Doxapram depolarized the hyperpolarized RMP of these oocytes, while uninjected oocytes showed no change. [1]
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| Animal Protocol |
Adult rats were used for minimum alveolar concentration (MAC) determination. The study was conducted in three stages. Stage 1: Baseline MAC for halothane was determined using the tail-clamp method. Stage 2: MAC was redetermined after a 1-hour 57-minute period. Stage 3: Halothane was returned to the smallest concentration that suppressed movement in all four rats from Stage 2. A doxapram infusion was started at 80 mg·kg⁻¹·h⁻¹ (8 mL/h of vehicle) for 15 minutes and then decreased to 20 mg·kg⁻¹·h⁻¹ (2 mL/h of vehicle) for the remainder of the experiment. After 15 minutes at 20 mg·kg⁻¹·h⁻¹, MAC was determined again. The total time for Stage 3 was 2 hours 17 minutes. Doxapram hydrochloride injection (20 mg/mL in water with 0.9% benzyl alcohol as preservative) was used for the infusion. [1]
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| References |
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| Additional Infomation |
A short-acting central respiratory stimulant. (From Martindale Pharmacopoeia, 30th edition, page 1225)
See also: Doxapram hydrochloride (note moved to). Doxapram is thought to stimulate ventilation by inhibiting baseline membrane potassium conductance in Type I glomus cells of the carotid bodies, leading to membrane depolarization, L-type Ca²⁺ channel activation, Ca²⁺ influx, and neurotransmitter release. TASK-1 and TASK-3 channels are expressed in carotid bodies and brainstem and are inhibited by acidic pH and hypoxia; they are plausible molecular targets for the ventilatory effects of doxapram. The carboxy terminal domain of TASK-1 appears important for doxapram inhibition based on chimera studies. Doxapram inhibits TASK-1 approximately two orders of magnitude more potently than TASK-3. The lack of effect of doxapram on halothane MAC suggests that TASK-1 and TASK-3 do not mediate halothane-induced immobility, even though volatile anesthetics enhance TASK channel function. Doxapram has a slowly reversible effect on TASK-1, TASK-1/TASK-3 heterodimer, and TASK-1-containing chimeras, which may explain its prolonged interaction with its effector site. [1] |
| Molecular Formula |
C24H33CLN2O3
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|---|---|
| Molecular Weight |
432.9834
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| Exact Mass |
432.217
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| CAS # |
7081-53-0
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| Related CAS # |
Doxapram;309-29-5
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| PubChem CID |
64648
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| Appearance |
White to off-white solid powder
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| Melting Point |
217-219°
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| LogP |
3.786
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
487
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
ZOMBFZRWMLIDPX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H30N2O2.ClH.H2O/c1-2-26-19-22(13-14-25-15-17-28-18-16-25)24(23(26)27,20-9-5-3-6-10-20)21-11-7-4-8-12-21/h3-12,22H,2,13-19H2,1H31H1H2
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| Chemical Name |
2-Pyrrolidinone, 1-ethyl-4-(2-(4-morpholinyl)ethyl)-3,3-diphenyl-, monohydrochloride, monohydrate
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| Synonyms |
AHR 619 AHR-619 AHR619
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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) |
DMSO : ≥ 55 mg/mL (~127.03 mM)
H2O : ~25 mg/mL (~57.74 mM) |
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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 | 2.3096 mL | 11.5479 mL | 23.0958 mL | |
| 5 mM | 0.4619 mL | 2.3096 mL | 4.6192 mL | |
| 10 mM | 0.2310 mL | 1.1548 mL | 2.3096 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 |
| NCT04430790 | Recruiting | Drug: Doxapram Drug: Placebo |
Apnea of Prematurity Respiratory Insufficiency |
Erasmus Medical Center | June 15, 2020 | Phase 3 |
| NCT02171910 | Completed | Drug: Doxapram Drug: Placebo |
Sedation Hypoxia |
Helsinki University Central Hospital | October 2016 | Phase 4 |
| NCT00389909 | Completed | Drug: Doxapram | Premature Infants Apnea |
Jean Michel Hascoet | November 2006 | Phase 4 |
| NCT00477451 | Completed Has Results | Drug: Inhaled alprazolam 2 mg Drug: IV doxapram |
Treatment of Induced Panic Attack | Alexza Pharmaceuticals, Inc. | May 2007 | Phase 2 |
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