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| 5mg |
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Purity: ≥98%
Pitolisant HCl (formerly also known as BF2.649; BF2649; Ciproxidine; Wakix) is a nonimidazole-based inverse agonist of the recombinant human histamine H3 receptor approved in 2019 for the treatment of excessive daytime sleepiness in adults with narcolepsy. It activates H3 receptor with Ki of 0.16 nM. Histamine H3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. On the stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a Ki value of 0.16 nM and as an inverse agonist with an EC50 value of 1.5 nM and an intrinsic activity approximately 50% higher than that of ciproxifan. Its in vitro potency was approximately 6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.
| ln Vitro |
Pitolisant (BF2.649) exhibits competitive antagonistic behavior, with a Ki value of 0.16 nM and an inverse EC50, when it comes to stimulating the binding of guanosine 5'-O-(3-[35S]thio)triphosphate to this receptor. The agonist value is 1.5 nM, and the intrinsic activity is roughly 50% higher than that of ciproxifene. Pitolisant has an IC50 value of 26.4±4.5 nM, which is sufficient to displace [125I]iodoproxyfan binding on mouse brain cortical membranes. Pitolisant's derived Ki value is 14±1 nM, based on the radioligand's Kd value of 161±9 pM. Pitolisant, with an IC50 value of 4.2±0.2 nM, displaces [125I]iodoproxyfan binding on the membrane of rat glioma C6 cells that are stably expressing human H3 receptors. Pitolisant's derived Ki value is 2.7±0.5 nM, based on the radioligand's Kd value of 50±4 pM. With a Hill coefficient close to 1 and an IC50 value of 330±68 nM, pitolisant progressively reverses this process, yielding a Ki value of 17±4 nM. With an EC50 value of 1.5±0.1 nM, pitolisant reduces basal specific [35S]GTPγS binding to membranes in a dose-dependent manner, with a maximum impact equal to 75±1% of basal specific binding [1].
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| ln Vivo |
Immobility time in the FST was also considerably impacted by a single dosage of LY170053 (2 mg/kg bw) given 30 minutes prior to a single dose of Pitolisantat (10 mg/kg). When the above medication sequence was subsequently given to mice, the length of immobility was statistically substantially longer than when the time for controls was measured in the footsie test. Moreover, it lessens motor activity. However, in contrast to the locomotor levels in a control group administered Pitolisant alone, the results obtained after 15 administrations of both drugs (Pitolisant 10 mg/kg bw, LY170053 2 mg/kg bw after 30 minutes, and LY170053 2 mg/kg bw after 4 hours) in subchronic treatment showed that administration of Pitolisant followed by LY170053 balanced the locomotor activity of mice. More notably, in the mouse forced swim test, this medication combination dramatically shortened immobility time to levels attained by the control group [one-way ANOVA; F(3,20)=4.226, P=0.0181][2]. Rats administered 10 mg/kg of pitolisant during the conditioning phase spent 502±94 seconds on the paired texture; this number did not differ statistically from the control group, suggesting that pitolisant does not support location preference [3].
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| References |
[1]. Ligneau X, et al. BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology. J Pharmacol Exp Ther. 2007 Jan;320(1):365-75.
[2]. Dudek M, et al. H3 histamine receptor antagonist pitolisant reverses some subchronic disturbances induced by LY170053 in mice. Metab Brain Dis. 2016 Oct;31(5):1023-9. [3]. Uguen M, et al. Preclinical evaluation of the abuse potential of Pitolisant, a histamine H? receptor inverse agonist/antagonist compared with CRL 40476. Br J Pharmacol. 2013 Jun;169(3):632-44 |
| Molecular Formula |
C17H27CL2NO
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|---|---|
| Molecular Weight |
332.3084
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| CAS # |
903576-44-3
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| Related CAS # |
Pitolisant;362665-56-3;Pitolisant oxalate;362665-57-4
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| SMILES |
ClC1=CC=C(CCCOCCCN2CCCCC2)C=C1.[H]Cl
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| InChi Key |
XLFKECRRMPOAQS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H26ClNO.ClH/c18-17-9-7-16(8-10-17)6-4-14-20-15-5-13-19-11-2-1-3-12-19;/h7-10H,1-6,11-15H2;1H
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| Chemical Name |
1-(3-(3-(4-Chlorophenyl)propoxy)propyl)piperidine hydrochloride
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| Synonyms |
FUB-649, BF-2649; B F2649; FUB649, BF2649; FUB 649; BF2.649; Pitolisant, Tiprolisant; Pitolisant HCl; Pitolisant hydrochloride
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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 : ~100 mg/mL (~300.92 mM)
DMSO : ≥ 43 mg/mL (~129.40 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.52 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 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.52 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 50 mg/mL (150.46 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0092 mL | 15.0462 mL | 30.0924 mL | |
| 5 mM | 0.6018 mL | 3.0092 mL | 6.0185 mL | |
| 10 mM | 0.3009 mL | 1.5046 mL | 3.0092 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.
Effect of Pitolisant (10 mg·kg−1, i.p.) or Modafinil (120 mg·kg−1, i.p.) on dopamine levels in microdialysates of rat nucleus accumbens core.Br J Pharmacol.2013 Jun;169(3):632-44. |
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Effects of Pitolisant, Modafinil or cocaine on spontaneous locomotor activity in male Wistar rats.Br J Pharmacol.2013 Jun;169(3):632-44. |
Effects of Pitolisant, Modafinil, cocaine or nicotine on the acquisition of place preference in male Wistar rats.Br J Pharmacol.2013 Jun;169(3):632-44. |
Effect of a Pitolisant (5 mg·kg−1, i.p.) pretreatment on the time course (A) and cumulated horizontal locomotor activity over 90 min (B) of vehicle or cocaine-treated (10 mg·kg−1, s.c.) mice.Br J Pharmacol.2013 Jun;169(3):632-44. |
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(A) Group mean infusions of Pitolisant (filled circles), saline (empty circles) and of cocaine (filled squares).Br J Pharmacol.2013 Jun;169(3):632-44. |
(A) Mean percent cocaine lever presses as a function of Pitolisant or cocaine dose.Br J Pharmacol.2013 Jun;169(3):632-44. |
Effect of Pitolisant and morphine chronic treatment on body weight (A) and withdrawal symptoms 48 h following last administration.Br J Pharmacol.2013 Jun;169(3):632-44. |
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Effects of acute or repeated administrations of Pitolisant (10 mg·kg−1, i.p.) or Modafinil (64 mg·kg−1, i.p.) on locomotor activity in male Wistar rats.Br J Pharmacol.2013 Jun;169(3):632-44. |
Conditioned hyperlocomotion elicited by Modafinil in the cue-associated environment 72 h after five locomotor recording sessions in male Wistar rats.Br J Pharmacol.2013 Jun;169(3):632-44. |
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