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].

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].

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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Administration of Pitolisant alone (10 mg/kg b.w., i.p.), either as a single dose or for 15 consecutive days, did not significantly affect the duration of immobility in the forced swim test (FST) in mice, indicating no intrinsic antidepressant- or depressant-like effect under these conditions. [2]
Pitolisant alone (10 mg/kg b.w., i.p.) had no effect on locomotor activity in mice after either single or subchronic (15-day) administration. [2]
Pitolisant alone (10 mg/kg b.w., i.p.) did not significantly affect spontaneous activity measured over 20 hours in mice using an RFID system. [2]
Subchronic co-administration of Pitolisant (10 mg/kg b.w., i.p.) with olanzapine (2x2 mg/kg b.w., i.p.) for 15 days reversed the olanzapine-induced increase in immobility time in the FST, bringing it back to the level of the control group. [2]
Subchronic co-administration of Pitolisant with olanzapine reversed the olanzapine-induced reduction in locomotor activity. [2]
Subchronic co-administration of Pitolisant with olanzapine compensated for the disturbances in spontaneous activity (measured over 20h) induced by olanzapine alone, particularly increasing motility during the dark phase and the following light phase. [2]
Subchronic co-administration of Pitolisant (10 mg/kg b.w., i.p.) with olanzapine (2x2 mg/kg b.w., i.p.) for 14 days prevented the olanzapine-induced increase in serum triglyceride levels, resulting in levels comparable to the control group. Pitolisant administered alone had no effect on triglyceride levels. [2]

Forced Swim Test (FST) and Locomotor Activity: Mice received intraperitoneal (i.p.) injections. Pitolisant (10 mg/kg body weight) was suspended in 1% Tween 80. In the combination group, Pitolisant was administered 15 minutes before olanzapine (2 mg/kg b.w.). For subchronic studies, drugs were administered once daily in the morning (approx. 9:00 a.m.) for 15 days; the olanzapine and olanzapine+Pitolisant groups received an additional olanzapine dose in the afternoon (approx. 1:00 p.m.). FST and locomotor activity tests were performed 30 minutes after the morning injection on day 1 (acute) and day 15 (subchronic). [2]
Spontaneous Activity (RFID monitoring): Mice were subcutaneously implanted with an RFID transmitter. Spontaneous activity was monitored continuously for 20 hours (from 1:00 p.m. on day 14 to 9:00 a.m. on day 15) in group-housed cages during subchronic treatment. [2]
Triglyceride Measurement: After 14 days of subchronic drug administration (same regimen as above), mice were euthanized by cervical dislocation on day 16. Blood was collected after decapitation, serum was obtained by centrifugation, and triglyceride levels were determined using standard enzymatic spectrophotometric assays. [2]

The literature indicates that in healthy volunteers, concurrent administration of pitorisone and olanzapine did not result in a significant change in plasma drug concentrations compared to administration of either drug alone. [2]

[1]. 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]. H3 histamine receptor antagonist pitolisant reverses some subchronic disturbances induced by LY170053 in mice. Metab Brain Dis. 2016 Oct;31(5):1023-9.

[3]. 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.

See also: Pitolisan (with active ingredient).

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Pitolisan is a selective histamine H₃ receptor inverse agonist that enhances histaminergic activity in the brain. [2]
At the time of this publication, Pitolisan was in a Phase III clinical trial for the treatment of conditions such as narcolepsy, Parkinson's disease, and obstructive sleep apnea/hypopnea, for its wakefulness-inducing effect. [2]
Pitolisan also has cognitive-enhancing activity, making it a potential therapeutic target for cognitive disorders such as schizophrenia. [2]
This study suggests that Pitolisan may be a promising adjunct to olanzapine for the treatment of sedation, depression-like symptoms, and metabolic disturbances (e.g., elevated triglycerides) that may occur at the onset of antipsychotic therapy. [2]

C17H27CL2NO

332.3084

331.146

903576-44-3

Pitolisant;362665-56-3;Pitolisant oxalate;362665-57-4

11551689

White to off-white solid powder

4.905

1

2

8

21

235

0

XLFKECRRMPOAQS-UHFFFAOYSA-N

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

1-(3-(3-(4-Chlorophenyl)propoxy)propyl)piperidine hydrochloride

FUB-649, BF-2649; B F2649; FUB649, BF2649; FUB 649; BF2.649; Pitolisant, Tiprolisant; Pitolisant HCl; Pitolisant hydrochloride

2934.99.9001

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.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~100 mg/mL (~300.92 mM)
DMSO : ≥ 43 mg/mL (~129.40 mM)

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.

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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.

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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.

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 (Please use freshly prepared in vivo formulations for optimal results.)