Pizotifen primarily targets 5-HT2 serotonin receptors and has a high affinity for the 5-HT1C binding site. It also acts as an antihistamine. Its antimigraine activity is attributed to its antagonist activity at serotonin receptors, which are involved in the regulation of vascular tone and pain pathways. Its antagonism of 5-HT2 receptors prevents serotonin-induced vasoconstriction and may reduce the frequency and severity of migraine attacks. It also exhibits antihistamine activity.

Pizotifen (BC-105) is a strong antagonist of the 5-HT2 receptor that has a high affinity for the binding region of the 5-HT1C [1]. Pizotifen is an anti-5-HT2A receptor antagonist that prevents platelet aggregation generated by ADP that is increased by serotonin [2].
Pizotifen demonstrates potent antagonist activity at 5-HT2 receptors in vitro. Its binding affinity (Ki) for the 5-HT2 receptor and the 5-HT1C binding site has been characterized in radioligand binding assays. It exhibits high affinity for these targets. Its antihistamine activity is also evident in vitro. As a serotonin receptor antagonist, it inhibits serotonin-induced cellular responses. Detailed quantitative data are limited in publicly available sources.

Placental weight was considerably reduced after pethidine at 0.6 and 1.2 mg/kg and solely at the intermediate dose of pethidine; fetal weight was significantly lowered at all administered doses of benzotifen (BC-105). Later on, it was greatly alleviated. There was no difference observed between the treated and control groups in terms of implantation, viable pregnancies, stillbirths, resorptions, and external, skeletal, and visceral abnormalities. There was no discernible difference between the treatment group's and the negative control group's number of chromosomal abnormalities in the mice's bone marrow cells. Testing for micronuclei revealed no rise in micronucleus frequency as compared to controls. Following two increased dosages of bentifen maleate (BC-105) and pethidine, the mitotic index was reduced in comparison to the control group [3].
Pizotifen demonstrates in vivo efficacy in the prophylaxis of migraine headaches. It has been used clinically as an antimigraine agent. It has had reported success in patients with polycythemia vera. The compound is administered orally, typically at doses of 0.5-1 mg, 1-3 times daily. Its therapeutic effects are attributed to serotonin receptor antagonism and antihistamine activity.

Serotonin receptor binding assays are performed using membranes prepared from cells expressing recombinant 5-HT2 receptors or from brain tissue. Radioligand binding studies use [3H]-ketanserin (5-HT2A) or [3H]-mesulergine (5-HT2C) as labeled ligands. Membrane preparations are incubated with varying concentrations of Pizotifen and a fixed concentration of radioligand in binding buffer for 60-120 minutes. Non-specific binding is determined using excess unlabeled ligand (e.g., methysergide or mianserin). Bound radioactivity is measured by scintillation counting after filtration through GF/B filters. IC50 and Ki values are calculated by non-linear regression.

Cellular 5-HT2 receptor antagonism is evaluated in cell lines expressing recombinant 5-HT2 receptors (e.g., HEK-293 cells transfected with 5-HT2A or 5-HT2C). Cells are cultured in appropriate media and treated with Pizotifen at various concentrations (0.1-100 μM). Functional assays measure receptor-mediated calcium mobilization (using Fluo-4 or Fura-2) or IP3 accumulation. The compound's antagonist activity is assessed by its ability to inhibit serotonin-induced calcium responses. Cell viability is assessed using MTT or LDH assays. Each experiment includes known serotonin receptor antagonists (e.g., ketanserin, ritanserin) as controls.

In vivo studies are conducted in animal models of migraine, such as the nitroglycerin-induced migraine model in rodents. Pizotifen is administered orally or intraperitoneally at doses typically ranging from 0.1-10 mg/kg. Behavioral assessments include pain-related behaviors (e.g., facial grooming, head shaking). For polycythemia vera research, effects on hematological parameters are evaluated. Sample sizes typically range from 8-12 animals per group. Clinical efficacy has been established in human trials for migraine prophylaxis.

Absorption, Distribution and Excretion
Following oral administration of Pizotifen, the absorption half-life in adult men is 0.5 to 0.8 hours, with near-complete absorption (80%). Peak plasma concentration is reached 5 hours after administration, with an absolute bioavailability of 78%. Approximately one-third of the total oral dose is excreted in feces. Less than 1% of the total dose is excreted unchanged in the urine, while up to 55% is excreted as metabolites. The volume of distribution of Pizotifen in an adult male is 833 liters, and the volume of distribution of its N-glucuronide conjugate is 70 liters. Metabolism/Metabolites Pizotifen is extensively metabolized in the liver, primarily via N-glucuronidation to produce the major metabolite, the N-glucuronide conjugate. The N-glucuronide conjugate accounts for at least 50% of plasma radioactivity and 60-70% of urinary radioactivity.

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Biological Half-Life
The elimination half-life of Pizotifen and its N-glucuronide conjugate is approximately 23 hours.

Pizotifen has a molecular weight of 295.44 g/mol and a molecular formula of C19H21NS. Purity: ≥98%. It is administered orally. Pharmacokinetic parameters: it is absorbed from the gastrointestinal tract, metabolized in the liver, and excreted renally. Half-life is approximately 20-30 hours. Bioavailability is not fully characterized. The compound is clinically used for migraine prophylaxis.

Protein Binding
Pizotifen has a plasma protein binding rate of >90%.
Pizotifen is generally well-tolerated at therapeutic doses. Common adverse effects may include drowsiness, weight gain, dry mouth, and dizziness. It may cause sedation, which can be managed by dose titration. It is contraindicated in patients with glaucoma and urinary retention. Standard toxicology studies have demonstrated an acceptable safety profile. It is approved for clinical use in many countries for migraine prophylaxis.

[1]. 5-HT2 receptor antagonists and migraine therapy. J Neurol. 1991;238 Suppl 1:S45-52.

[2]. The antidepressant 5-HT2A receptor antagonists pizotifen and cyproheptadine inhibit serotonin-enhanced platelet function. PLoS One. 2014 Jan 23;9(1):e87026.

[3]. Teratological and cytogenetical evaluation of two antihistamines (pipethiadene and pizotifen maleate) in mice. Agents Actions. 1988 Apr;23(3-4):376-8.

Pizotifen is a benzo[4,5]cycloheptaphylene compound, chemically named 9,10-dihydro-4H-benzo[4,5]cycloheptaphylene(4-methylene)-1-methylpiperidine, with a double bond at the 4-position of its N-methylpiperidine moiety. It is a sedative antihistamine with potent serotonin antagonism and weak antimuscarinic activity. It is commonly used in the form of malate for the treatment of migraines and prevention of cluster headaches. It acts as a serotonin antagonist, muscarinic antagonist, and histamine antagonist. Its function is associated with piperidine compounds. It is the conjugate base of Pizotifen(1+). Pizotifen belongs to the class of antiamines and is associated with cyproheptadine. Pizotifen is a potent serotonin and tryptamine antagonist and has been used for many years for the prevention of migraines. In addition to its sedative and appetite-stimulating effects, it also has weak anticholinergic, antihistamine, and antikinin effects. Some patients treated with Pizotifen have developed tolerance after long-term use. Numerous studies have shown that Pizotifen has potential antidepressant effects, independent of its anti-migraine effects. Although some studies suggest that the mechanism of action of Pizotifen may be similar to that of classic tricyclic antidepressants, its complete antidepressant mechanism has not been fully elucidated. Pizotifen hydrochloride is the active ingredient in Sandomigran, a drug used to prevent migraines. Sandomigran is available in several countries but has not yet been approved by the US FDA or EMA.
A serotonin antagonist used to treat migraines and vascular headaches.

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Drug Indications
Indicated for the preventive treatment of migraines.

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Mechanism of Action
Although its mechanism of action is not fully understood, it is speculated that Pizotifen works by inhibiting the peripheral effects of serotonin and histamine, thereby increasing intracranial vascular permeability and plasma kinin exudation, and altering the pain threshold of migraines. Pizotifen attenuates serotonin-induced intracranial vasoconstriction signals and serotonin-enhanced platelet function and aggregation by blocking 5-HT receptors. There is evidence that it also inhibits the peripheral effects of bradykinin. Pizotifen may inhibit platelet reuptake of serotonin, thereby affecting the tone of extracranial arteries and reducing their passive dilation. The appetite-stimulating effect of Pizotifen may be due to its action at the metabolic level rather than direct stimulation of the appetite center.
Pizotifen is also known as Pizotyline and BC-105. Its chemical name is 4-(9,10-Dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-methylpiperidine. It is a potent 5-HT2 receptor antagonist with high affinity for the 5-HT1C binding site. It is used as an antimigraine agent. It has also been used in polycythemia vera. It is approved for clinical use in many countries.

C19H21NS

295.4417

295.139

15574-96-6

Pizotifen malate;5189-11-7

27400

White to off-white solid powder

1.2±0.1 g/cm3

436.7±45.0 °C at 760 mmHg

140-142°C

217.9±28.7 °C

0.0±1.0 mmHg at 25°C

1.631

6.13

0

2

0

21

406

0

FIADGNVRKBPQEU-UHFFFAOYSA-N

InChI=1S/C19H21NS/c1-20-11-8-15(9-12-20)19-16-5-3-2-4-14(16)6-7-18-17(19)10-13-21-18/h2-5,10,13H,6-9,11-12H2,1H3

1-methyl-4-(6-thiatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),4,10,12-pentaen-2-ylidene)piperidine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO : ~20 mg/mL (~67.70 mM)
H2O : < 0.1 mg/mL

Solubility in Formulation 1: ≥ 2 mg/mL (6.77 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 20.0 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.

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Solubility in Formulation 2: ≥ 2 mg/mL (6.77 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 20.0 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 3: ≥ 2 mg/mL (6.77 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 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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