5-HT₂ Receptor; hERG current ( IC50 = 0.11 μM )
Ketanserin tartrate primarily targets the 5-HT2A serotonin receptor, where it acts as a potent antagonist. It also exhibits significant selectivity for the human 5-HT1Dα receptor. Furthermore, ketanserin functions as an antagonist at the α1-adrenergic receptor. It has been reported to have a high affinity for multiple G protein-coupled receptors, including serotonin receptors. Ketanserin is a selective SR-2/SR-1C antagonist and has been used to distinguish between SR-1D and SR-1B subtypes. It also inhibits the hERG current with an IC50 of 0.11 μM.

Ketanserin (R49945; KJK945) causes the contractile responses of isolated rat caudal arteries, dog carotid, basilar, coronary, and gastrosplenic arteries, as well as dog saphenous and gastrosplenic veins, to be dose-dependently inhibited by 5-hydroxytryptamine. Postjunctional alpha adrenergic activation-induced contractions of the canine saphenous vein and rat caudal arteries are inhibited by ketanserin. In the stomach of a perfused guinea pig, ketanserin depresses and, in some experiments, reverses the vasoconstrictor response to 5-hydroxytryptamine. In the lateral geniculate nucleus, it is discovered that ketonerin reduces the excitatory reactions triggered by norepinephrine, an alpha 1-adrenoceptor-mediated response. In the lateral geniculate nucleus, ketanserin increases rather than decreases the inhibitory effect of 5-HT. In rat ventricular myocytes, ketanserin significantly increases action potential duration (APD) at 50% repolarization by 218% and APD at 90% repolarization by 256%. No discernible effects are seen on other action potential parameters. Ketanserin inhibits the charge area of Ito in a concentration- and time-dependent manner, as measured by integration, with an EC50 of 8.3 μM. With an EC50 of 11.2 μM, ketanserin also inhibits Ito and sustained current (ISus) in a dose-dependent manner. It has no discernible effect on the L-type calcium current or the inward rectifier potassium current.
In vitro, ketanserin causes dose-dependent inhibition of 5-hydroxytryptamine-induced contractile responses in isolated rat caudal arteries, dog carotid, basilar, coronary, and gastrosplenic arteries, as well as dog saphenous and gastrosplenic veins. It inhibits postjunctional alpha adrenergic activation-induced contractions of the canine saphenous vein and rat caudal arteries. In the perfused guinea pig stomach, ketanserin depresses and sometimes reverses the vasoconstrictor response to 5-hydroxytryptamine. In the lateral geniculate nucleus, ketanserin reduces excitatory reactions triggered by norepinephrine (an alpha 1-adrenoceptor-mediated response). In rat ventricular myocytes, ketanserin significantly increases action potential duration at 50% repolarization by 218% and at 90% repolarization by 256%. Ketanserin inhibits the charge area of Ito in a concentration- and time-dependent manner with an EC50 of 8.3 μM, and also inhibits Ito and with an EC50 of 11.2 μM.

Ketanserin (R49945; KJK945) does not significantly affect the tail-flick test, but it does produce dose-dependent antinociception in the hot-plate and acetic acid-induced writhing tests, with ED50 values (95% confidence limit) of 1.51 and 0.62 mg/kg, respectively.

The serotonergic receptor antagonist 3-(2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl)-2,4-[1H,3H]quinazolinedione Ketanserin (R 41 468) caused a dose-dependent inhibition on the contractile responses to 5-hydroxytryptamine of isolated rat caudal artery, canine basilar, carotid, coronary and gastrosplenic arteries, canine gastrosplenic veins (threshold 10(-10)-10(-9) M) and canine saphenous veins (threshold 10(-8) M). In concentrations up to 2.5 X 10(-5) M, it did not have agonistic properties. From 10(-8) M on, R 41 468 inhibited the contractions of rat caudal arteries and canine saphenous veins caused by postjunctional alpha adrenergic activation. In the rat caudal artery, R 41 468, in concentrations which did not affect the contractile response to norepinephrine, abolished the amplifying effect of low concentrations of 5-hydroxytryptamine on alpha adrenergic activation. In the canine saphenous vein, R 41 468 did not affect the prejunctional inhibitory effect of 5-hydroxytryptamine during sympathetic nerve stimulation. In the perfused guinea-pig stomach, R 41 468 depressed and in certain experiments reversed the vasoconstrictor response to 5-hydroxytryptamine. In isolated perfused kidneys from both normotensive and spontaneously hypertensive rats, R 41 468, in concentrations which did not depress vasoconstrictor responses to exogenous norepinephrine, inhibited those to 5-hydroxytryptamine. The compound caused a dose-related reduction in aortic blood pressure in unanesthetized spontaneously hypertensive rats, which was larger and occurred at lower concentrations, than in control animals. These results demonstrate that R 41 468 is a potent antagonist of the vasoconstrictor effects of 5-hydroxytryptamine, in particular of its amplifying effect on threshold amounts of norepinephrine, which may help explain its antihypertensive properties[J Pharmacol Exp Ther . 1981 Jul;218(1):217-30.].
The receptor binding profile of ketanserin can be assessed using radioligand binding assays. Membranes prepared from rat or human tissues are incubated with a radiolabeled ligand specific for the 5-HT2A receptor (e.g., [³H]ketanserin or [³H]LSD) and varying concentrations of unlabeled ketanserin. Non-specific binding is determined in the presence of an excess of a competing ligand. After incubation, the samples are filtered through glass fiber filters, and the retained radioactivity is measured by liquid scintillation counting. The Ki or IC50 values for ketanserin displacement are calculated from competition binding curves.

The HEK 293 cell line, which has been established to express hERG channels consistently, is cultivated in Dulbecco's modified Eagles medium (DMEM) that has been enhanced with 10% foetal bovine serum and 400 μg/mL G418. The HEK 293 cell line is cultured in DMEM supplemented with 10% foetal bovine serum and 100 μg/mL hygromycin, which is responsible for the stable expression of recombinant human cardiac KCNQ1/KCNE1 channel current (I_Ks). On a glass coverslip, cells are seeded for electrophysiology. HEK 293 cells are used to create the mutant hERG channels, which are then temporarily expressed using 10 μL of Lipofectamine 2000 in combination with 4 μg of hERG mutant cDNA in pCDNA3 vector.
To evaluate the cellular effects of ketanserin, various cell types expressing serotonin receptors or α1-adrenergic receptors can be used. Cells are treated with increasing concentrations of ketanserin, and functional responses are measured. For example, the inhibition of 5-HT-induced calcium mobilization or phosphoinositide hydrolysis can be assessed. In rat ventricular myocytes, the effects on action potential duration and ion currents (Ito) can be measured using patch-clamp electrophysiology. The IC50 or EC50 values for these effects are determined from dose-response curves.

5 mg/kg
Rats: A total of 155 male Sprague-Dawley rats, weighing 180–220 g, that are 2 months old and free of specific pathogens are utilized. The following six groups are randomly assigned to the rats: The solvent control no-stress group (0.9% physiological saline group, CON group); the 5-HT_1A receptor antagonist (MDL73005) PS group (MDL-PS group, n=30); the 5-HT_2A receptor agonist (DOI) PS group (DOI-PS group, n=30); the 5-HT_2A receptor antagonist (Ketanserin) PS group (Ketan-PS group, n=30); and the PS only group (PS group, n=30). The six subgroups (n=5 each) comprising the DPAT-PS, MDL-PS, DOI-PS, Ketan-PS, and PS groups are further separated based on the amount of time that elapses between the stress and analysis: immediately following the stress, as well as 0.5, 1, 2, 6, and 24 hours after the stress. The five members of the CON group eat normally. Ketanserin, diluted in 0.9% physiological saline, is injected intraperitoneally at a dose of 5 mg/kg one hour prior to each stress exposure for the Ketan-PS group.

Ketanserin tartrate has a molecular weight of 545.52 and a molecular formula of C22H22FN3O3 · C4H6O6. Its purity is >98% by HPLC. It is soluble in DMSO (30 mg/mL) and water (5 mg/mL). The compound is a white solid and should be stored at -20°C for up to 2 years from the date of purchase. Solutions in DMSO may be stored at -20°C for up to 3 months.

Ketanserin tartrate is an approved antihypertensive drug that is well tolerated. It is effective in lowering blood pressure in essential hypertension. Ketanserin inhibits platelet aggregation. In rat ventricular myocytes, high concentrations of ketanserin significantly increase action potential duration. The compound also inhibits the hERG current with an IC50 of 0.11 μM, indicating a potential for cardiac side effects at high concentrations.

[1]. The 5-HT2 antagonist Ketanserin is an open channel blocker of human cardiac ether-à-go-go-related gene (hERG) potassium channels. Br J Pharmacol. 2008 Oct;155(3):365-73.

[2]. Investigation of cyclooxygenase and signaling pathways involved in human platelet aggregation mediated by synergistic interaction of various agonists. Drug Des Devel Ther. 2015 Jul 6;9:3497-506.

[3]. Antiserotonergic properties of terguride in blood vessels, platelets, and valvular interstitial cells. J Pharmacol Exp Ther. 2012 Feb;340(2):369-76.

[4]. Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress. Neural Regen Res. 2016 Sep;11(9):1471-1479.

Ketanserin belongs to the quinazoline class of compounds, with the structure quinazoline-2,4(1H,3H)-dione, substituted at the 3-position with 2-[4-(p-fluorobenzoyl)piperidin-1-yl]ethyl. It possesses various pharmacological activities, including α-adrenergic antagonist, serotonergic antagonist, antihypertensive agent, cardiovascular agent, and EC 3.4.21.26 (prolyl oligopeptidase) inhibitor. Ketanserin belongs to the quinazoline, piperidine, organofluorine, and aromatic ketone classes. It is the conjugate base of Ketanserin(1+). Ketanserin has been investigated for the treatment of septic shock, severe sepsis, and diabetic foot ulcers. Ketanserin is a quinazoline derivative and a 5-hydroxytryptamine (5-HT) receptor subtype 2 (5-HTR2) antagonist, with potential antihypertensive and antiplatelet activities. After administration, Ketanserin binds to 5-HTR2 and inhibits its mediated signaling, thereby suppressing serotonin-dependent vasoconstriction and platelet activation. It is a selective serotonin receptor antagonist with weak adrenergic receptor blocking activity. This drug effectively lowers blood pressure in patients with essential hypertension and inhibits platelet aggregation. It is well-tolerated, especially effective in elderly patients. See also: Ketanserin tartrate (note moved to).
Ketanserin tartrate (R-41468; Vulketan) is an approved antihypertensive drug. It is a selective serotonin 5-HT2A receptor antagonist (IC50 = 6.3 nM). It has been used to disrupt the hallucinogenic effects of psilocybin and to explore cognitive effects of the 5-HT2A receptor. Ketanserin is also an α1-adrenergic receptor antagonist. It is available for research use only and is not intended for human or veterinary applications in a research setting.

C26H28FN3O9

545.52

545.18

C, 57.25; H, 5.17; F, 3.48; N, 7.70; O, 26.40

83846-83-7

Ketanserin; 74050-98-9

3822

White to off-white solid powder

780.4ºC at 760 mmHg

425.8ºC

0.239

1

5

5

29

627

0

FC1C([H])=C([H])C(=C([H])C=1[H])C(C1([H])C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])N2C(N([H])C3=C([H])C([H])=C([H])C([H])=C3C2=O)=O)C([H])([H])C1([H])[H])=O

KMTLTEVOQLMYRS-UHFFFAOYSA-N

InChI=1S/C22H22FN3O3.C4H6O6/c23-17-7-5-15(6-8-17)20(27)16-9-11-25(12-10-16)13-14-26-21(28)18-3-1-2-4-19(18)24-22(26)29;5-1(3(7)8)2(6)4(9)10/h1-8,16H,9-14H2,(H,24,29);1-2,5-6H,(H,7,8)(H,9,10)

2,3-dihydroxybutanedioic acid;3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-1H-quinazoline-2,4-dione

Ketanserin tartrate; KJK-945; R49945; KJK945; Ketanserin tartrate; 83846-83-7; 3-(2-(4-(p-Fluorobenzoyl)-1-piperidinyl)ethyl)-2,4(1H,3H)-quinazolinedione L-tartrate; 2,3-dihydroxybutanedioic acid;3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-1H-quinazoline-2,4-dione; SMR000058867; KETANSERINTARTRATE; 3-[2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl]-2,4[1H,3H]-quinazolinedione tartrate; SR-01000002994; R 49945; KJK 945; R-49945

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)

DMSO: ~125 mg/mL (~229.1 mM)
H2O: ~6 mg/mL (~11.0 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.81 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 20.8 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: ≥ 2.08 mg/mL (3.81 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 20.8 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: ≥ 2.08 mg/mL (3.81 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 20.8 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.)