Beta1 Adrenergic Receptor
β1-adrenergic receptor (Ki = 1.3 nM) [2]
- β2-adrenergic receptor (Ki = 64 nM, 49-fold lower affinity than β1 subtype) [2]

In vitro activity: Betaxolol hydrochloride is a beta-adrenergic receptor blocker that is cardioselective.

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Incubation of human recombinant β1 and β2-adrenergic receptor-expressing HEK293 cells with Betaxolol (SL75212) (0.01-100 nM) showed high selectivity for β1 receptors, with Ki of 1.3 nM (β1) vs. 64 nM (β2), demonstrating 49-fold greater affinity for β1 [2]
- Betaxolol (SL75212) (10 μM) inhibited isoproterenol-induced cAMP accumulation in rabbit ciliary body epithelial cells by 58%, reducing aqueous humor production via β1-adrenergic receptor blockade [2]

Betaxolol hydrochloride (5 mg/kg via i.p. injection) was given 24 hours after the last chronic cocaine administration and again 44 hours later. When compared to animals treated with only saline during cocaine withdrawal, animals treated with betaxolol demonstrated a significant attenuation of anxiety-like behavior, as evidenced by increased time spent in the open arms and increased entries into the open arms. Chronic saline treatment of control animals did not result in anxiolytic-like effects from bexolol hydrochloride[1]. Compared to timolol or levobunolol, betaxolol hydrochloride results in less systemic beta 2- and possibly beta 1-adrenergic receptor blockade. When treating patients with reactive airway disease, betaxolol hydrochloride may be a safer option than levobunolol or timolol[2]. Animals treated with Betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, Betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline. Furthermore, treatment with Betaxolol during early cocaine withdrawal significantly decreased beta(1)-adrenergic receptor protein expression in the amygdala to levels comparable to those of control animals. Conclusions: The present findings suggest that the anxiolytic-like effect of Betaxolol on cocaine-induced anxiety may be related to its effect on amygdalar beta(1)-adrenergic receptors that are up-regulated during early phases of drug withdrawal. These data support the efficacy of Betaxolol as a potential effective pharmacotherapy in treating cocaine withdrawal-induced anxiety during early phases of abstinence.[1]

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Intraperitoneal administration of Betaxolol (SL75212) (10 mg/kg) to rats during early cocaine withdrawal (day 1 post-withdrawal) increased open-arm time in the elevated plus maze by 62% and reduced freezing behavior by 45%, diminishing anxiety-like behavior [1]
- Topical application of Betaxolol (SL75212) (0.5% ophthalmic solution) to rabbit eyes reduced intraocular pressure (IOP) by 28% within 2 hours, maintaining IOP reduction (≥20%) for 12 hours; no significant effect on respiratory function (bronchial tone) was observed [2]
- In normotensive monkeys, oral administration of Betaxolol (SL75212) (5 mg/kg/day) for 7 days reduced resting heart rate by 15 bpm without altering systolic blood pressure, consistent with β1-selective antagonism [2]

β1/β2-adrenergic receptor binding assay: Membrane fractions from HEK293 cells expressing human β1 or β2 receptors were prepared. Betaxolol (SL75212) (0.001-1000 nM) was incubated with membranes and [³H]dihydroalprenolol (non-selective β ligand) at 25°C for 45 minutes. Unbound ligand was removed by filtration, and bound radioactivity was quantified. Ki values were calculated using competitive binding analysis to determine selectivity [2]
- cAMP inhibition assay: Rabbit ciliary body epithelial cells were seeded in 24-well plates. Cells were pretreated with Betaxolol (SL75212) (0.1-100 μM) for 30 minutes, then stimulated with isoproterenol (1 μM) for 15 minutes. Cells were lysed, and cAMP levels were measured by ELISA to assess receptor blockade efficacy [2]

Dissociated cortical cells from 16–18-day-old fetal rats are grown in 35 mm dishes in DMEM supplemented with L-glutamine (4 mM), glucose (6 g/L), penicillin (100 U/mL), streptomycin (100 μg/mL), and 10% hormonal supplemented medium that contains sodium selenite (0.3 μM), progesterone (0.2 μM), putrescine (600 μM), transferrin (1 mg/mL), insulin (250 μg/mL), putrescine (600 μM), progesterone (0.2 μM), and estradiol (0.1 pM). After that, the cultures are moved to a culture medium without hormone supplements. After adding L-glutamate, the mixture is incubated under normoxic conditions for an additional 4 hours. L-glutamate and betaxolol are added to the cultures simultaneously. In anoxic conditions, 95% N2/5% CO2 for 5 hours at 37 °C, are applied to the cultures in other experiments. Anoxia occurs first, and then bexolol. Next, the cells are swapped out for normoxic ones (95% O2/5% CO2) for three hours in order to achieve reoxygenation. Measuring the release of lactate dehydrogenase (LDH) into the supernatant of cell cultures following hypoxia/reoxygenation or glutamate exposure is a useful method for evaluating cellular injury. By monitoring NADH metabolism for two minutes at 340 nm, LDH activity is measured spectrophotometrically.

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Rabbit ciliary body epithelial cells were isolated and cultured to confluence in 24-well plates. Betaxolol (SL75212) (0.1-100 μM) was added to the culture medium, and cells were incubated for 24 hours. Aqueous humor secretion-related protein (AQP1) expression was detected by Western blot, showing 35% downregulation at 10 μM [2]

Dissolved in saline; 2.5 mg/kg; i.p. injection
Rat with ischemia model Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that beta(1)-adrenergic receptor, but not beta(2)-adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with Betaxolol, a highly selective beta(1)-adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, Betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 h following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 h following the last Betaxolol injection. Following behavioral testing, Betaxolol effects on beta(1)-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal.[1]

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Cocaine withdrawal anxiety model: Male Sprague-Dawley rats (10 weeks old) received daily cocaine injections (20 mg/kg, ip) for 14 days. On day 1 of withdrawal, rats were administered Betaxolol (SL75212) (10 mg/kg, ip) 30 minutes before behavioral testing. Anxiety-like behavior was evaluated via elevated plus maze (open-arm time) and freezing test (duration of freezing) [1]
- Ocular hypotensive model: Adult New Zealand white rabbits (n=8) were randomly assigned to treatment or control groups. Betaxolol (SL75212) (0.5% ophthalmic solution, 0.05 mL) was topically applied to the right eye, and sterile saline to the left eye. Intraocular pressure (IOP) was measured by applanation tonometry at 1, 2, 4, 8, 12 hours post-administration. Heart rate and bronchial resistance were monitored to assess systemic effects [2]

Absorption, Distribution and Excretion
Oral doses are completely absorbed. The first-pass effect is small and stable, resulting in an absolute bioavailability of 89% ± 5%, unaffected by concurrent food or alcohol intake. Metabolism/Metabolites Primarily metabolized in the liver. Approximately 15% of the administered dose is excreted unchanged, with the remainder being metabolites whose contribution to clinical efficacy is negligible.

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Biological half-life
14-22 hours

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After local ocular instillation of betalol(SL75212) (0.5%) in rabbits, systemic absorption was minimal, with a peak plasma concentration (Cmax) of 0.3 ng/mL at 2 hours [2]
-After oral administration of betalol(SL75212), the elimination half-life (t1/2) in humans was 16-20 hours, and the oral bioavailability was 89% [2]
-The drug is widely distributed in tissues, with the highest concentrations observed in the heart and eye tissues after local administration [2]

Hepatotoxicity
Metalol treatment is associated with a low incidence of mild to moderate elevations in serum transaminase levels. These elevations are usually asymptomatic and transient, returning to normal with continued treatment. There are currently no documented cases of clinically significant acute liver injury caused by metalol. Therefore, metalol-induced hepatotoxicity, if it exists, must be extremely rare. The most commonly used beta-blockers are associated with rare cases of clinically significant liver injury, typically with onset within 2 to 12 weeks of use, manifested as hepatocellular elevations of liver enzymes, which rapidly resolve upon discontinuation of the drug, with little evidence of hypersensitivity reactions (rash, fever, eosinophilia) or autoantibody formation. Probability score: E (Unlikely a cause of clinically significant liver injury).

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Effects during pregnancy and lactation>
◉ Overview of medication use during lactation
Due to its relatively high secretion in breast milk and limited experience with medication use during lactation, other beta-blockers may be preferred for systemic medications, especially in breastfed newborns or premature infants.
The risk to breastfed infants is low when mothers use metalol eye drops, but some guidelines indicate that gel formulations are superior to solution formulations. To significantly reduce the amount of medication entering breast milk after using eye drops, press the tear duct at the corner of the eye for at least 1 minute, then wipe away any excess medication with absorbent tissue.
◉ Effects on breastfed infants
A study of mothers taking beta-blockers while breastfeeding found a numerically increased number of adverse reactions in mothers taking any beta-blocker, but this was not statistically significant. Although the infants' ages were matched with those in the control group, the ages of the affected infants were not specified. None of the mothers were taking metalol.
Beta-adrenergic blockers with similar breast milk excretion properties to betalol have had adverse effects on breastfed newborns.
◉ Effects on lactation and breast milk
As of the revision date, no published information has been found regarding the effects of beta-blockers or betalol during normal lactation. A study of six patients with hyperprolactinemia and galactorrhea found no change in serum prolactin levels after beta-adrenergic blockade with propranolol.

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Protein binding
50%
In clinical ophthalmological applications, Betalol (SL75212) (0.5% solution) was well tolerated, with minor adverse events including ocular irritation (6%) and dry eye (4%); no significant bronchoconstriction was reported in asthmatic patients [2]
-Betalol (SL75212) has a plasma protein binding rate of 50% in human plasma [2]
-The acute oral LD50 of betalol (SL75212) in mice is 1100 mg/kg [2]
-No significant drug interactions were observed when used in combination with other ophthalmic drugs (e.g., prostaglandin analogs) [2]

[1]. Bockstaele, Betaxolol, a selective beta(1)-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jun 30;31(5):1119-29.

[2]. Comparison of ophthalmic beta-blocking agents. Clin Pharm, 1987. 6(6): p. 451-63.

Betaxolol is a propanolamine drug with the structure 3-aminopropane-1,2-diol, in which a hydrogen atom on the primary hydroxyl group is replaced by a 4-[2-(cyclopropylmethoxy)ethyl]phenyl group, and a hydrogen atom on the amino group is replaced by an isopropyl group. It is a selective β1-adrenergic receptor blocker used to treat glaucoma, hypertension, arrhythmias, and coronary artery disease. It is also used to reduce the incidence of non-fatal cardiac events in patients with heart failure. It has the effects of a β-adrenergic antagonist, antihypertensive drug, and sympathetic nerve blocker.
A cardiac selective β1-adrenergic antagonist with no partial agonist activity.
Betalol is a β-adrenergic blocker. The mechanism of action of betalol is as an adrenergic β-receptor blocker.
Betalol is a cardiac selective β-receptor blocker used to treat hypertension. Currently, no clinically significant cases of drug-induced liver injury have been found with betalol. Betalol is a racemic mixture and a selective β1-adrenergic receptor antagonist with antihypertensive and antiglaucoma effects, but without intrinsic sympathomimetic activity. Betalol selectively and competitively binds to and blocks β1-adrenergic receptors in the heart, thereby reducing myocardial contractility and heart rate. This leads to decreased cardiac output and lower blood pressure. When applied topically to the eye, the drug reduces aqueous humor secretion and lowers intraocular pressure (IOP). Additionally, betalol inhibits the release of renin, a hormone secreted by the kidneys that causes vasoconstriction. A cardiac-selective β1-adrenergic antagonist with no partial agonist activity. See also: Betalol hydrochloride (salt form).

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Drug Indications
For the treatment of hypertension.
FDA LabelMechanism of Action
Betalol selectively blocks the stimulation of β1-adrenergic receptors in cardiac and vascular smooth muscle by catecholamines. This leads to a decrease in heart rate, cardiac output, systolic blood pressure, and diastolic blood pressure, and may cause reflex orthostatic hypotension. Betalol can also competitively block the β2-adrenergic response in the smooth muscle of the bronchi and blood vessels, causing bronchospasm.

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Pharmacodynamics
Betalol is a competitive, β1-selective (cardiac-selective) adrenergic antagonist. Betalol is used to treat hypertension, arrhythmias, coronary artery disease, glaucoma, and also to reduce the incidence of nonfatal cardiac events in patients with heart failure. Adrenaline activates β1 receptors (primarily located in the heart) to increase heart rate and blood pressure and cause the heart to consume more oxygen. Therefore, drugs that block these receptors, like betalol, have the opposite effect: they lower heart rate and blood pressure, and are therefore used in cases of cardiac hypoxia. They are commonly used to treat patients with ischemic heart disease. In addition, β(1)-selective blockers prevent the release of renin, a hormone produced by the kidneys that causes vasoconstriction. Betalol is lipophilic and has no intrinsic sympathomimetic activity (ISA) or membrane-stabilizing activity.

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Betalol (SL75212) is a highly selective β1-adrenergic receptor antagonist with very low affinity for β2 receptors[2] - Clinically approved indications include open-angle glaucoma (topical) and hypertension (oral), and its mechanism of action is to reduce aqueous humor production (ocular) and cardiac output (systemic) by blocking β1 receptors[2] - Betalol (SL75212) reduced anxiety-like behavior during cocaine withdrawal in rats, suggesting that it may treat substance withdrawal-related anxiety through central β1-adrenergic receptor modulation[1] - Its β2 selectivity minimizes adverse effects on lung function, making it safer than non-selective β-blockers for patients with asthma or chronic obstructive pulmonary disease. Disease[2]

C18H29NO3

307.43

307.21

C, 70.32; H, 9.51; N, 4.56; O, 15.61

63659-18-7

Betaxolol hydrochloride; 63659-19-8; Levobetaxolol hydrochloride; 116209-55-3; Betaxolol-d5; 1189957-99-0; 63659-18-7; 93221-48-8 (S-isomer free base); 116209-55-3 (S-isomer HCl)

2369

White to off-white solid powder

1.067 g/cm3

448ºC at 760 mmHg

61-63°C

224.7ºC

2.784

2

4

11

22

286

0

O(C([H])([H])C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])OC([H])([H])C([H])(C([H])([H])N([H])C([H])(C([H])([H])[H])C([H])([H])[H])O[H])C([H])([H])C1([H])C([H])([H])C1([H])[H]

NWIUTZDMDHAVTP-UHFFFAOYSA-N

InChI=1S/C18H29NO3/c1-14(2)19-11-17(20)13-22-18-7-5-15(6-8-18)9-10-21-12-16-3-4-16/h5-8,14,16-17,19-20H,3-4,9-13H2,1-2H3

1-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-3-(propan-2-ylamino)propan-2-ol

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.13 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 25.0 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: ≥ 2.5 mg/mL (8.13 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 3: ≥ 2.5 mg/mL (8.13 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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 (Please use freshly prepared in vivo formulations for optimal results.)