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Pitolisant (formerly BF2.649; Tiprolisant; BF2649; Ciproxidine; Wakix) is a novel, potent and selective nonimidazole inverse agonist of the recombinant human histamine H3 receptor with Ki of 0.16 nM. The medication was authorized in 2019 to treat narcolepsy in adults who experience excessive daytime sleepiness. It has been demonstrated that histamine H3 receptor inverse agonists increase histaminergic neuron activity in the brain, which in turn enhances alertness and cognitive function. With an EC50 value of 1.5 nM and an intrinsic activity that was roughly 50% greater than ciproxifan, BF2.649 exhibited competitive antagonistic and inverse agonistic properties upon the stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding to this receptor. At the rodent receptor, its in vitro potency was roughly six times lower. Oral bioavailability coefficient (ratio of plasma areas under the curve after oral and intravenous administrations, respectively) in mice 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. The drug raised the levels of acetylcholine and dopamine in prefrontal cortex microdialysates in rats. It was found to significantly increase wakefulness in cats, at the expense of sleep states, and to improve the fast cortical rhythms of the electroencephalogram, which are linked to increased vigilance. A promnesiant effect was observed with respect to either scopolamine-induced or spontaneous forgetting on the two-trial object recognition test in mice. These preclinical findings imply that BF2.649 is a promising medication candidate for the treatment of wakefulness, memory problems, and other cognitive disorders.
| Targets |
H3 receptor ( Ki = 0.16 nM ); H3 receptor ( EC50 = 1.5 nM )
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| ln Vitro |
Pitolisant (BF2.649) exhibits competitive antagonistic (Ki = 0.16 nM) and inverse agonistic (EC50 = 1.5 nM) behaviors upon stimulation of guanosine 5′-O-(3-[35S]thio)triphosphate binding to this receptor. Its intrinsic activity is approximately 50% greater than that of ciproxifan. Pitolisant has an IC50 value of 26.4±4.5 nM, which is sufficient to remove [125I]iodoproxyfan binding from mouse brain cortical membranes. TaKing into account the Kd value of the radioligand (161±9 pM), the deduced Ki value for Pitolisant is 14±1 nM. Pitolisant, with an IC50 value of 4.2±0.2 nM, displaces [125I]iodoproxyfan binding from the membranes of rat glioma C6 cells that express the human H3 receptor stably. Pitolisant's calculated Ki value is 2.7±0.5 nM when the radioligand's Kd value of 50±4 pM is taken into account. With a Hill coefficient near unity and an IC50 value of 330±68 nM, pitolisant gradually reverses this response, resulting in a Ki value of 17±4 nM. Pitolisant reduces basal-specific [35S]GTPγS binding to membranes in a dose-dependent manner; the maximal effect is equivalent to 75±1% of basal-specific binding, with an EC50 value of 1.5±0.1 nM[1].
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| ln Vivo |
The single dose of Olanzapine (2 mg/kg b.w.) given 30 minutes prior to a single dose of Pitolisantat (10 mg/kg) also has a significant impact on the immobility time in the FST. When the previously mentioned drug sequence is given to mice again, the length of immobility is statistically significantly longer than when it was measured in the FST control group. Furthermore, it lowered locomotor activity. The results of subchronic treatment, on the other hand, indicate that the administration of Pitolisant followed by that of Olanzapine equalized the locomotor activity in mice. This is in contrast to the level of motility in the control group, which receives only Pitolisant. Pitolisant was administered at a dose of 10 mg/kg b.w. for fifteen minutes, and Olanzapine at a dose of 2 mg/kg b.w. for four hours. More significantly, this combination of medications lowers immobility time in the forced swim test in mice to a level attained in the control group [one-way ANOVA; F(3,20)=4.226,P=0.0181].[2] Pitolisant (10 mg/kg)-administered rats remained on the paired texture for 502±94 s during the conditioning phase; this value was not statistically different from controls, suggesting that Pitolisant did not support place preference[3].
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| Enzyme Assay |
There are assays for [35S]GTPγS binding. Homogenized in an ice-cold buffer (50 mM Tris/HCl, pH 7.4), CHO-K1 cells that stably express the human H3 receptor (~400 fmol/mg protein) are used. The final pellet is resuspended in 50 volumes of buffer after homogenates are centrifuged twice (20,000g for 10 min at 4°C). Membranes containing 550 μg of protein are pretreated with 1 U/mL of adenosine deaminase and then incubated at 25°C for 60 minutes with 0.1 nM [35S] GTPηS and the medications to be examined in a final volume of 1 mL of assay buffer, which contains 10 μM GDP, 50 mM Tris/HCl, 50 mM NaCl, 5 mM MgCl2, and 0.02% bovine serum albumin at pH 7.4. Using 10 μM nonradioactive GTPγS, the nonspecific binding is ascertained. Filtration through GF/B glass fiber filters quickly and under vacuum ends incubations. Following an ice-cold water wash, liquid scintillation spectrometry is used to quantify the radioactivity trapped on the filters. The measure of competitive antagonism is the same as well. Essentially, membranes (10 μg of protein) from HEK-293 cells that stably express the human H3 receptor (~600 fmol/mg protein) are preincubated with Pitolisant in the buffer (50 mM Tris/HCl, pH 7.4, 10 mM MgCl2, 100 mM NaCl, and 10 μM GDP) in a 96-well microplate. This is done with mild stirring at room temperature (19–20°C) for 30 minutes before 0.1 nM [35S]GTPηS (final volume 200 μL) is added. Nonradioactive GTPγS at a concentration of 10 μM is used to measure the nonspecific binding. On a Multiscreen MAFCOB50 microplate, incubations carried out in triplicate are terminated after 30 minutes by quick filtration under vacuum. Liquid scintillation spectrometry counts radioactivity that has become trapped on filters[1].
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| Animal Protocol |
Mice: The study makes use of adult female Albino Swiss mice weighing 20–22 g. A 1% Tween 80 suspension contains either olanzapine or pitolisant. An acute experiment begins 30 minutes before the compounds or vehicle are injected intraperitoneally (i.p.). Pitolisant and Olanzapine are given to the group that receives them 15 minutes apart. Subchronic treatment is done at about 9:00 am (0.2 mL Tween to control group, Pitolisant-10 mg/kg b.w. to Pitolisant group, Olanzapine-2 mg/kg b.w. to Olanzapine group, Pitolisant-10 mg/kg b.w. and Olanzapine after 15 min-2 mg/kg b.w. to Pitolisant+Olanzapine group) and at about 1:00 pm (Olanzapine group and Pitolisant+Olanzapine group).
Rats: Male Wistar rats (220-300 g) receive vehicle (methylcellulose 1%, p.o.), Pitolisant (10 mg/kg, p.o.) or D-amphetamine (2.5 mg/kg, i.p. in saline). The nucleus accumbens is removed, weighed, frozen in liquid nitrogen, and kept at -80°C after they are beheaded ninety minutes later. A 0.4 N perchloric acid/2.7 mM EDTA solution in 1 mL is used to homogenize the tissues. HPLC coupled with electrochemical detection is used to analyze the supernatants following centrifugation (8000 rpm, 20 min, 4°C). Dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA), and dopamine (DA) tissue concentrations are measured, and the corresponding ratios (DOPAC/DA, HVA/DA) are computed.
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| References |
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| Molecular Formula |
C17H26CLNO
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|---|---|
| Molecular Weight |
295.8474
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| Exact Mass |
295.17
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| Elemental Analysis |
C, 69.02; H, 8.86; Cl, 11.98; N, 4.73; O, 5.41
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| CAS # |
362665-56-3
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| Related CAS # |
Pitolisant hydrochloride; 903576-44-3; Pitolisant oxalate; 362665-57-4
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| Appearance |
Solid powder
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| SMILES |
C1CCN(CC1)CCCOCCCC2=CC=C(C=C2)Cl
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| InChi Key |
NNACHAUCXXVJSP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H26ClNO/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
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| Chemical Name |
1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine
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| Synonyms |
FUB-649; BF2649; FUB649; BF-2649; FUB 649; BF2.649; B F2649; Pitolisant; Tiprolisant; Pitolisant HCl; Pitolisant hydrochloride
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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 |
| 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: ~66 mg/mL (~198.6 mM)
Water: ~66 mg/mL Ethanol: ~66 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.45 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 25.0 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: ≥ 2.5 mg/mL (8.45 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (8.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.3801 mL | 16.9005 mL | 33.8009 mL | |
| 5 mM | 0.6760 mL | 3.3801 mL | 6.7602 mL | |
| 10 mM | 0.3380 mL | 1.6900 mL | 3.3801 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 |
| NCT05458128 | Active Recruiting |
Drug: Pitolisant | Idiopathic Hypersomnia Excessive Daytime Sleepiness |
Harmony Biosciences, LLC | August 19, 2022 | Phase 3 |
| NCT05156047 | Active Recruiting |
Drug: Pitolisant Oral Tablet Drug: Placebo oral tablet |
Idiopathic Hypersomnia | Harmony Biosciences, LLC | May 25, 2022 | Phase 3 |
| NCT05156047 | Active Recruiting |
Drug: Pitolisant Oral Tablet Drug: Placebo oral tablet |
Idiopathic Hypersomnia | Harmony Biosciences, LLC | May 25, 2022 | Phase 3 |
| NCT04886518 | Active Recruiting |
Drug: Pitolisant Oral Tablet Drug: Placebo oral tablet |
Myotonic Dystrophy 1 Excessive Daytime Sleepiness |
Harmony Biosciences, LLC | June 28, 2021 | Phase 2 |
| NCT04257929 | Active Recruiting |
Drug: Pitolisant oral tablets Drug: Placebo oral tablet |
Prader-Willi Syndrome | Harmony Biosciences, LLC | December 9, 2020 | Phase 2 |
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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