Ketanserin (R41468) 74050-98-9_5-HT Receptor_GPCR & G Protein_Signaling Pathways_Products

Ketanserin (R41468; Vulketan; KJK-945; R-41468), an aprroved antihypertensive drug, is a potent and specific 5-HT2A serotonin receptor antagonist with a Ki of 2.5 nM for rat and human 5-HT2A. Additionally, it can be applied to distinguish between 5-HT1D and 5-HT1B receptor subtypes. When postjunctional alpha adrenergic activation occurs, ketanserin prevents the contraction of the canine saphenous vein and the rat caudal artery.

Physicochemical Properties

Molecular Formula

C22H22FN3O3

Molecular Weight

395.43

Exact Mass

395.164

Elemental Analysis

C, 66.82; H, 5.61; F, 4.80; N, 10.63; O, 12.14

CAS #

74050-98-9

Related CAS #

Ketanserin tartrate; 83846-83-7

PubChem CID

3822

Appearance

White to off-white solid powder

Density

1.3±0.1 g/cm3

Melting Point

227-235°C

Index of Refraction

1.593

LogP

3.21

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

627

Defined Atom Stereocenter Count

SMILES

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

InChi Key

FPCCSQOGAWCVBH-UHFFFAOYSA-

InChi Code

InChI=1S/C22H22FN3O3/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/h1-8,16H,9-14H2,(H,24,29)

Chemical Name

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

Synonyms

R41468; Ketanserin tartrate; Ketanserinum; Ketaserin; Ketanserina; Ketanserine; 3-(2-(4-(4-Fluorobenzoyl)piperidin-1-yl)ethyl)quinazoline-2,4(1H,3H)-dione;R 41468; Vulketan; R-41468

HS Tariff Code

2934.99.9001

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)

Biological Activity

Targets

5-HT2A ( Ki = 2.5 nM ); 5-HT2C (Rat) ( Ki = 50 nM ); 5-HT2C (Human) ( Ki = 100 nM )

ln Vitro

In vitro activity: Ketanserin 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.[1] 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.[2] 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. [3]

ln Vivo

The involvement of 5-HT2 receptors in pain transmission was investigated in mice. Subcutaneous administration of the selective 5-HT2 receptor antagonist ketanserin produced dose-dependent antinociception in the hot-plate and acetic acid-induced writhing tests with ED50 values (95% confidence limit) of 1.51 (1.13-1.89) and 0.62 (0.10-1.40) mg/kg, respectively, but was without any significant effect on the tail-flick test. Pretreatment with the catecholamine depletors 6-hydroxydopamine (2.5 micrograms, i.c.v.) or alpha-methyl-p-tyrosine (200 mg/kg, s.c.), or the serotonin synthesis inhibitor p-chlorophenylalanine methylester (200 mg/kg, s.c.), resulted in a significant decrease in the antinociceptive effect of ketanserin. Likewise, intrathecal (i.t.) administration of 1 microgram/mouse of idazoxan (an alpha 2-antagonist), methysergide (mixed 5-HT1, and 5-HT2 antagonist) or ketanserin also reversed the antinociceptive effect of s.c. administered ketanserin. The results of this work indicate that 5-HT2 receptors located supraspinally may inhibit descending nociceptive neurotransmission. In addition, these studies suggest that 5-HT2 receptors located at the spinal level modulate nociception.[4]

Ketanserin exhibits dose-dependent antinociception with ED50 values (95% confidence limit) of 1.51 and 0.62 mg/kg, respectively, but has no discernible effect on the tail-flick test in the hot-plate and acetic acid-induced writhing tests.

Enzyme Assay

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[1].

Cell Assay

The HEK 293 cell line, which has been established to express hERG channels consistently, is cultivated in Dulbecco's modified Eagle's 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 (IKs). 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.

Animal Protocol

Rat: A total of 180–220 g male Sprague-Dawley rats, 2 months old, free of specific pathogens, are used. The following six groups are created at random from the rats: 10-OH-DPAT 5-HT_1A receptor agonist PS group (DPAT-PS group, n = 30); 5-HT_1A receptor antagonist (MDL73005) PS group (MDL-PS group, n = 30); 5-HT_2A receptor agonist (DOI) PS group (DOI-PS group, n = 30); 5-HT_2A receptor antagonist (Ketanserin) PS group (Ketan-PS group, n = 30); the solvent control no-stress group (0.9% physiological saline group, CON group); 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.

References

[1]. J Pharmacol Exp Ther . 1981 Jul;218(1):217-30.

[2]. Neuropharmacology . 1985 Apr;24(4):265-73.

[3]. Circ Res . 1994 Oct;75(4):711-21.

[4]. Brain Res . 1991 Mar 15;543(2):335-40.

Additional Infomation

Ketanserin is a member of the class of quinazolines that is quinazoline-2,4(1H,3H)-dione which is substituted at position 3 by a 2-[4-(p-fluorobenzoyl)piperidin-1-yl]ethyl group. It has a role as an alpha-adrenergic antagonist, a serotonergic antagonist, an antihypertensive agent, a cardiovascular drug and an EC 3.4.21.26 (prolyl oligopeptidase) inhibitor. It is a member of quinazolines, a member of piperidines, an organofluorine compound and an aromatic ketone. It is a conjugate base of a ketanserin(1+).
Ketanserin has been investigated for the treatment of Septic Shock, Severe Sepsis, and Diabetic Foot Ulcer.
Ketanserin is a quinazoline derivative and serotonin (5-hydroxytryptamine, 5HT) receptor subtype 2 (5-HTR2) antagonist with potential antihypertensive and antiplatelet activities. Following administration, ketanserin binds to and inhibits the signaling mediated by 5-HTR2, which inhibits serotonin-dependent vasoconstriction and platelet activation.
A selective serotonin receptor antagonist with weak adrenergic receptor blocking properties. The drug is effective in lowering blood pressure in essential hypertension. It also inhibits platelet aggregation. It is well tolerated and is particularly effective in older patients.
See also: Ketanserin Tartrate (annotation moved to).

Solubility Data

Solubility (In Vitro)

DMSO: 2~16.7 mg/mL (5.1~42.2 mM)

Water: <1 mg/mL

Ethanol: <1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 1.67 mg/mL (4.22 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 16.7 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: ≥ 1.67 mg/mL (4.22 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 16.7 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 3: ≥ 1.67 mg/mL (4.22 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 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

Solubility in Formulation 4: ≥ 0.5 mg/mL (1.26 mM) (saturation unknown) in 10% DMF 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 5: 4%DMSO + 40%PEG300 + 4%Tween 80 + 52%ddH2O: 1.0mg/ml (2.53mM)

Solubility in Formulation 6: 6.25 mg/mL (15.81 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.5289 mL	12.6445 mL	25.2889 mL
	5 mM	0.5058 mL	2.5289 mL	5.0578 mL
	10 mM	0.2529 mL	1.2644 mL	2.5289 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.

PeptideDB

Ketanserin (R41468) 74050-98-9

CAS No.: 74050-98-9

Physicochemical Properties

Biological Activity

Solubility Data