Levobetaxolol HCl (AL-1577A) 116209-55-3_Adrenergic Receptor_GPCR & G Protein_Signaling Pathways_Products

Levobetaxolol HCl ((S)-Betaxolol; AL 1577A; Betaxon; AL-1577A) is the hydrochloride salt of Levobetaxolol which is a potent beta-adrenergic receptor inhibitor/beta blocker with antihypertensive effects. Levobetaxolol, the S-isomer of betaxolol, shows a higher affinity at cloned human β1 and β2 receptors with Ki value of 0.76 nM and 32.6 nM, respectively. It is used to treat conditions like glaucoma by reducing the pressure inside the eye. The functional activities of cloned human β1 and β2 receptors are potently antagonistic to Levobetaxolol. Levobetaxolol(Ki = 16.4 nM) is more potent than dextrobetaxolol (Ki = 2.97 μM) at inhibiting isoproterenol-induced cAMP production in human non-pigmented ciliary epithelial cells.

Physicochemical Properties

Molecular Formula

C18H30CLNO3

Molecular Weight

343.89

Exact Mass

343.191

Elemental Analysis

C, 62.87; H, 8.79; Cl, 10.31; N, 4.07; O, 13.96

CAS #

116209-55-3

Related CAS #

Betaxolol; 63659-18-7; Betaxolol hydrochloride; 63659-19-8

PubChem CID

60656

Appearance

White to off-white solid powder

Boiling Point

448ºC at 760 mmHg

Flash Point

224.7ºC

Vapour Pressure

8.26E-09mmHg at 25°C

LogP

3.586

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

286

Defined Atom Stereocenter Count

SMILES

Cl[H].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]

InChi Key

CHDPSNLJFOQTRK-LMOVPXPDSA-N

InChi Code

InChI=1S/C18H29NO3.ClH/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;1H/t17-;/m0./s1

Chemical Name

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

Synonyms

AL 1577A; (S)-Betaxolol hydrochloride; AL 1577A; Levobetaxolol hydrochloride; Levobetaxolol HCl; LEVOBETAXOLOL HYDROCHLORIDE; 116209-55-3; Betaxon; AL 1577A; (S)-Betataxolol hydrochloride; AL1577A; Levobetaxolol hydrochloride [USAN]; AL-1577A; AL1577A; Betaxon

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

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)

Biological Activity

Targets

β1-adrenergic receptor ( Ki = 0.76 nM ); β2-adrenergic receptor ( Ki = 32.6 nM )

ln Vitro

In vitro activity: Levobetaxolol has IC50s of 33.2 nM, 2970 nM, and 709 nM, respectively, and potently antagonizes functional activities at cloned human β1 and β2 receptors, as well as at guinea pig atrial β1, tracheal β2, and rat colonic β3 receptors. Levobetaxolol (Ki = 16.4 nM) is more potent than dextrobetaxolol (Ki = 2.97 μM) at inhibiting isoproterenol-induced cAMP production in human non-pigmented ciliary epithelial cells.[1] It has been demonstrated that topically applied Levobetaxolol can reach the back of the eye in sufficient amounts to shield retinal ganglion cells from a variety of insults. displacement by Levobetaxolol [³H] -nitrendipine for the rat cortex's L-type voltage-dependent calcium channel receptor, which has an IC50 of 29.5 μM. Levobetaxolol decreases the 45Ca²⁺ influx stimulated by NMDA by 47.3%. When applied topically, Levobetaxolol lessens the amplitude of the b-wave that results from ischaemia/reperfusion.[2]

ln Vivo

The pharmacological characteristics of levobetaxolol, a single active isomer of betaxolol, were determined and compared with activities of other beta-adrenoceptor antagonists. Levobetaxolol (43-fold beta1-selective) exhibited a higher affinity at cloned human beta1 (Ki = 0.76 nM) than at beta2 (Ki = 32.6 nM) receptors, while dextrobetaxolol was much weaker at both receptors. Levobetaxolol potently antagonized functional activities at cloned human beta1 and beta2 receptors, and also at guinea pig atrial beta1, tracheal beta2 and rat colonic beta3 receptors (IC50s = 33.2 nM, 2970 nM and 709 nM, respectively). Thus, levobetaxolol was 89-times beta1-selective (vs beta2). Levobetaxolol (Ki = 16.4 nM) was more potent than dextrobetaxolol (Ki = 2.97 microM) at inhibiting isoproterenol-induced cAMP production in human non-pigmented ciliary epithelial cells. Levobunolol and (l)-timolol had high affinities at beta1 and beta2 receptors but were considerably less beta1-selective than levobetaxolol. Levo-, dextro- and racemic-betaxolol exhibited little or no affinity, except at sigma sites and Ca2+-channels (IC50s > 1 microM), at 89 other receptor/ligand binding sites. Levobetaxolol exhibited a micromolar affinity for L-type Ca2+-channels. In conscious ocular hypertensive cynomolgus monkeys, levobetaxolol was more potent than dextrobetaxolol, reducing intraocular pressure by 25.9+/-3.2% at a dose of 150 microg/eye (n = 15-30). Quantitative [3H]-levobetaxolol autoradiography revealed high levels of binding to human ciliary processes, iris, choroid/retina, and ciliary muscles. In conclusion, levobetaxolol is a potent, high affinity and beta1-selective IOP-lowering beta-adrenoceptor antagonist.[1]

Levobetaxolol (150 mg/eye) is more potent than dextrobetaxolol, reducing intraocular pressure by 25.9% in conscious ocular hypertensive cynomolgus monkeys. [1] In a rat model of photic-induced retinopathy, Levobetaxolol (20 mg/kg) significantly protects retinal function and causes the RPE and outer nuclear layer to thicken. Levobetaxolol (20 mg/kg) increases the levels of bFGF and CNTF mRNA by a factor of ten and two, respectively. These trophic factors have been demonstrated to prevent retinal degeneration in several species. [3]

Animal Protocol

Rats were dosed (IP) with vehicle or levobetaxolol (10 and 20 mg kg(-1)) 48, 24 and 0 hr prior to exposure for 6 hr to fluorescent blue light. The electroretinogram (ERG) and retinal morphology were assessed after a 3 week recovery period. Evaluation of the ERG demonstrated significant protection of retinal function in levobetaxolol (20 mg kg(-1))-dosed rats compared to vehicle-dosed rats. Similarly, the RPE and outer nuclear layer were significantly thicker in levobetaxolol (20 mg kg(-1))-dosed rats compared to vehicle-dosed rats. To elucidate potential mechanism(s) of the neuroprotective activity of levobetaxolol, bFGF and CNTF mRNA levels in normal rat retinas were evaluated 12 hr after a single i.p. injection. Northern blot analysis of levobetaxolol treated retinas demonstrated a 10-fold up-regulation of bFGF and a two-fold up-regulation of CNTF mRNA levels, trophic factors that have been shown to inhibit retinal degeneration in a number of species. These studies suggest that levobetaxolol can be used as a novel neuroprotective agent to ameliorate retinopathy.[3]

20 mg/kg

Hypertensive cynomolgus monkeys

ADME/Pharmacokinetics

Absorption, Distribution and Excretion
Levobetaxolol is applied topically to the eye but some does reach systemic circulaton with a Tmax of 3 h.

Biological Half-Life
The mean half life of levobetaxolol is 20 h.

References

[1]. J Ocul Pharmacol Ther . 2001 Aug;17(4):305-17.

[2]. Brain Res Bull . 2004 Feb 15;62(6):525-8.

[3]. Exp Eye Res . 2002 Apr;74(4):445-53.

Additional Infomation

Levobetaxolol Hydrochloride is the hydrochloride salt form of levobetaxolol, the S-isomer of the -selective beta-1 adrenergic receptor antagonist betaxolol with anti-glaucoma activity and devoid of intrinsic sympathomimetic activity. When applied topically in the eye, levobetaxolol reduces aqueous humor secretion and lowers the intraocular pressure (IOP).
See also: Levobetaxolol (has active moiety).

Glaucoma is a chronic optic neuropathy in which retinal ganglion cells die over a number of years. The initiation of the disease and its progression may involve an ischaemic-like insult to the ganglion cell axons caused by an alteration in the quality of blood flow. Thus, to effectively treat glaucoma it may be necessary to counteract the ischaemic-like insult to the region of the optic nerve head. Studies on the isolated optic nerve suggest that substances that reduce the influx of sodium would be particularly effective neuroprotectants. Significantly, of the presently used antiglaucoma substances, only beta-blockers can reduce sodium influx into cells. Moreover, they also reduce the influx of calcium and this would be expected to benefit the survival of insulted neurones. Betaxolol is the most effective antiglaucoma drug at reducing sodium/calcium influx. Our electroretinographic data indicated that topical application of levobetaxolol to rats attenuated the effects of ischaemia/reperfusion injury. Timolol was also effective but to a lesser extent. Based on these data we conclude that beta-blockers may be able to blunt ganglion cell death in glaucoma, and that levobetaxolol may be a more effective neuroprotectant than timolol because of its greater capacity to block sodium and calcium influx.[2]

Solubility Data

Solubility (In Vitro)

DMSO: ~69 mg/mL (~200.6 mM)

Water: ~69 mg/mL (~200.6 mM)

Ethanol: ~69 mg/mL (~200.6 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.27 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.

Solubility in Formulation 2: ≥ 2.5 mg/mL (7.27 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.

Solubility in Formulation 3: 120 mg/mL (348.95 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.9079 mL	14.5395 mL	29.0791 mL
	5 mM	0.5816 mL	2.9079 mL	5.8158 mL
	10 mM	0.2908 mL	1.4540 mL	2.9079 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

Levobetaxolol HCl (AL-1577A) 116209-55-3

CAS No.: 116209-55-3

Physicochemical Properties

Biological Activity

Solubility Data