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| Targets |
β1-adrenoceptor ( IC50 = 0.8 nM )
Nebivolol targets the β1-adrenergic receptor (β1-AR), a G protein-coupled receptor activated by catecholamines. It acts as a selective β1-AR antagonist, blocking activation of adrenergic receptors by epinephrine, reversing its effects and lowering heart rate and blood pressure. Nebivolol shows Ki values of 0.88 nM at β1, 20 nM at β2, 44 nM at 5-HT1A, and 700 nM at 5-HT2 receptors. It also has mild vasodilating properties via the L-arginine/NO pathway. |
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| ln Vitro |
Nebivolol demonstrates high affinity and selectivity for beta 1-adrenergic receptor sites in a rabbit lung membrane preparation (Ki value = 0.9 nM and beta 2/beta 1 ratio = 50).[1] Nebivolol demonstrates selectivity for β1-adrenoceptors with a Ki(β2)/Ki(β1) value of 40.7, as determined by competition experiments to 3H-CGP 12.1777 when CGP 207.12 A (300 nM, Kiβ2) or ICI 118.551 (50 nM, Kiβ1) are present.[2] Nebivolol inhibits human endothelial cells (haECs) and coronary smooth muscle cells (haCSMCs) in a manner that is concentration- and time-dependent. After 7 days of treatment, a significant reduction in the cell growth of haCSMCs is observed with an IC50 of 6.1 μM. Additionally, the accelerated proliferation of haCSMCs stimulated by growth factors TGFβ, bFGF, and PDGF-BB is inhibited with IC50 values of 6.8 μM, 6.4 μM, and 7.7 μM, respectively. After giving haCSMCs a 10-to 5-microgram dose of nibevolol for 48 hours, 23% of the cells undergo moderate apoptosis, and the proportion of S-phase cells falls from 16% to 5%. HaCEs produce more NO during Nebivolol incubation, but endothelin-1 transcription and secretion are inhibited.[3]
In vitro, Nebivolol selectively inhibits β1-adrenoceptor with an IC₅₀ of 0.8 nM and shows IC₅₀ of 251 nM for β2-ARs. It has Ki values of 0.88 nM at β1, 20 nM at β2, 44 nM at 5-HT1A, 700 nM at 5-HT2, and 1160 nM at α1 receptors. The compound shows high selectivity for β1 over other adrenergic and serotonin receptors. Detailed in vitro data are available in pharmacological literature. |
| ln Vivo |
Nebivolol administration reduces myocardial apoptosis in rats with myocardial infarction (MI). This effect is mediated by regulation of NO and occurs first by intravenous injection within 10 minutes of reperfusion and then orally. Nebivolol decreases both total and localized apoptotic cardiomyocytes and considerably prevents variations in left ventricular (LV) pressure. Treatment with nevivolol slightly but not significantly lowers the mean blood pressure (MBP) in rats suffering from MI.[4]
In vivo, Nebivolol is used clinically for the treatment of hypertension and chronic heart failure. Human evidence shows that 5 mg reduces systolic blood pressure by 24±9 mm Hg. It blocks activation of adrenergic receptors, lowering heart rate and blood pressure. The compound also has mild vasodilating properties via the L-arginine/NO pathway. Nebivolol is a well-established therapeutic agent. |
| Enzyme Assay |
In vitro receptor binding assays for Nebivolol typically use membrane preparations from cells expressing human β1-AR or β2-AR. Radioligand binding is performed using [³H]-CGP12177 or [³H]-dihydroalprenolol as tracer. Membranes are incubated with radioligand and varying concentrations of Nebivolol in assay buffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl₂) at room temperature or 37°C for 60-90 minutes. Nonspecific binding is determined using excess propranolol. Bound radioactivity is measured by filtration and scintillation counting. Ki values are calculated from competition curves. Functional assays measure cAMP accumulation.
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| Cell Assay |
Nebivolol (10-7~10-5 M) is added to cells at varying concentrations for 1, 2, 4, 7, and 14 days. Bromodeoxyuridine (BrdU) incorporation is used to analyze cell proliferation, while PI or annexin V staining is used to identify cell apoptosis.
For cell-based assays, cells expressing β1-AR or β2-AR (e.g., CHO or HEK-293 transfectants) are cultured in DMEM with 10% FBS and selection antibiotics. Cells are seeded in 96-well plates and treated with Nebivolol at various concentrations (0.001-100 nM) for 15-30 minutes. Cells are stimulated with isoproterenol, and cAMP levels are measured by ELISA or AlphaScreen. IC₅₀ values for antagonist activity are calculated. Cell viability is assessed by standard assays. All treatments include vehicle controls and are performed in triplicate. |
| Animal Protocol |
Male Sprague Dawley rat myocardial infarction (MI) model
2.0 mg/kg Gastric gavage once daily In vivo, Nebivolol is typically administered orally to patients at doses of 2.5-10 mg daily. For animal studies, rodents are dosed orally or via other routes. Blood pressure and heart rate are measured using tail-cuff or telemetry methods. For hypertension models, animals are dosed at various regimens. Endpoints include blood pressure reduction, heart rate changes, and vascular function assessment. Blood samples are collected for pharmacokinetic analysis. All procedures follow institutional guidelines. |
| ADME/Pharmacokinetics |
Nebivolol HCl (MW 441.9, C₂₂H₂₅F₂NO₄·HCl) is a β1-AR antagonist with an IC₅₀ of 0.8 nM. It is 40-fold selective for β1 over β2-ARs. The compound is orally bioavailable. Nebivolol is metabolized in the liver. Detailed pharmacokinetic parameters (bioavailability, half-life, clearance) are available from clinical pharmacology literature. It is a well-established pharmaceutical agent.
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| Toxicity/Toxicokinetics |
Nebivolol is a clinically approved drug with an established safety profile. It is used for the treatment of hypertension and chronic heart failure. Common side effects include headache, fatigue, and dizziness. It is contraindicated in patients with bradycardia, heart block, and severe hypotension. The compound is available as a pharmaceutical product. Standard precautions for β-blocker use apply.
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| References | |
| Additional Infomation |
(S,R,R,R)-Nebivolol hydrochloride is a hydrochloride salt prepared by reacting (S,R,R,R)-nebivolol with an equivalent amount of hydrochloric acid. It contains (S,R,R,R)-nebivolol (1+). It is the enantiomer of (R,S,S,S)-nebivolol hydrochloride. It is a cardiac-selective adrenergic β1 receptor antagonist (β-blocker) that exerts its vasodilatory effect through the endothelial L-arginine/nitric oxide system. It is used to treat hypertension and chronic heart failure in elderly patients. See also: Nebivolol (containing the active fraction); Nebivolol hydrochloride; Valsartan (component).
Nebivolol is a clinically approved β1-adrenergic receptor antagonist for the treatment of hypertension and chronic heart failure. It uniquely combines β1-AR antagonism with endothelium-dependent vasodilation via the L-arginine/NO pathway. The compound is available as a pharmaceutical product in many countries. It is also available from chemical suppliers for research purposes. Its mechanism involves selective β1-AR blockade and NO-mediated vasodilation. |
| Molecular Formula |
C22H26CLF2NO4
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|---|---|
| Molecular Weight |
441.8960
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| Exact Mass |
441.151
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| Elemental Analysis |
C, 59.80; H, 5.93; Cl, 8.02; F, 8.60; N, 3.17; O, 14.48
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| CAS # |
152520-56-4
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| Related CAS # |
Nebivolol; 118457-14-0
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| PubChem CID |
24866733
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| Appearance |
White to off-white solid powder
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| Boiling Point |
600.5ºC at 760 mmHg
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| Melting Point |
220-222ºC
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| Flash Point |
316.9ºC
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| Vapour Pressure |
2.88E-15mmHg at 25°C
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| LogP |
3.556
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
483
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| Defined Atom Stereocenter Count |
4
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| SMILES |
Cl[H].FC1C([H])=C([H])C2=C(C=1[H])C([H])([H])C([H])([H])[C@]([H])(C([H])(C([H])([H])N([H])C([H])([H])[C@@]([H])([C@]1([H])C([H])([H])C([H])([H])C3C([H])=C(C([H])=C([H])C=3O1)F)O[H])O[H])O2
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| InChi Key |
JWEXHQAEWHKGCW-BIISKSHESA-N
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| InChi Code |
InChI=1S/C22H25F2NO4.ClH/c23-15-3-7-19-13(9-15)1-5-21(28-19)17(26)11-25-12-18(27)22-6-2-14-10-16(24)4-8-20(14)29-22;/h3-4,7-10,17-18,21-22,25-27H,1-2,5-6,11-12H2;1H/t17-,18-,21-,22+;/m0./s1
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| Chemical Name |
(1S)-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-[[(2S)-2-[(2R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl]amino]ethanol;hydrochloride
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| Synonyms |
Silostar; Bystolic; R 67145; R-67145; R67145; Nebivolol HCl; Nebivolol 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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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: 88~100 mg/mL (199.1~226.3 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.71 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.71 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 5% DMSO + 20% PEG300 + 5%Tween 80 + 70%ddH2O: 4.4mg/ml (9.96mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2630 mL | 11.3148 mL | 22.6296 mL | |
| 5 mM | 0.4526 mL | 2.2630 mL | 4.5259 mL | |
| 10 mM | 0.2263 mL | 1.1315 mL | 2.2630 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 |
| NCT05328310 | Active Recruiting |
Drug: Nebivolol | Hypertension | Korea University Anam Hospital | January 6, 2019 | Not Applicable |
| NCT05728632 | Active Recruiting |
Drug: Nebivolol Drug: Placebo |
Breast Cancer Cardiotoxicity |
Giulio Stefanini | January 1, 2019 | Phase 3 |
| NCT06104423 | Recruiting | Drug: Nebivolol 5 mg Drug: Ramipril 2.5/5/10 mg |
Hypertension | Menarini International Operations Luxembourg SA |
October 2, 2023 | Phase 4 |
| NCT06035978 | Not yet recruiting | Drug: Nebivolol Drug: Carvedilol |
Cardiovascular Diseases Heart Failure With Reduced Ejection Fraction |
University Hospital Ostrava | March 2024 | Phase 4 |
| NCT03778554 | Recruiting | Drug: Nebivolol Drug: Carvedilol Drug: Nebivolol |
Acute Myocardial Infarction ST Elevation Myocardial Infarction |
Bispebjerg Hospital | December 17, 2018 | Phase 4 |
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