-baclofen (STX209) Chemical Structure.png)
(R)-baclofen (formerly STX-209; STX209; STX 209), a derivative of gamma-aminobutyric acid, is a selective GABAB receptor agonist that has been primarily used to treat spasticity. Baclofen is a synthetic chlorophenyl-butanoic acid derivative used to treat spasms due to spinal cord damage and multiple sclerosis, muscle-relaxing. It acts at spinal and supraspinal sites, reducing excitatory transmission. GABAB receptors are metabotropic receptors which produce slow inhibitory signals.
Physicochemical Properties
| Molecular Formula | C10H12CLNO2 | |
| Molecular Weight | 213.66 | |
| Exact Mass | 213.055 | |
| CAS # | 69308-37-8 | |
| Related CAS # | 63701-55-3 | |
| PubChem CID | 44602 | |
| Appearance | White to off-white solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Boiling Point | 364.3±32.0 °C at 760 mmHg | |
| Melting Point | 171-174°C | |
| Flash Point | 174.1±25.1 °C | |
| Vapour Pressure | 0.0±0.9 mmHg at 25°C | |
| Index of Refraction | 1.577 | |
| LogP | 1.56 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 3 | |
| Rotatable Bond Count | 4 | |
| Heavy Atom Count | 14 | |
| Complexity | 191 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | C1=CC(=CC=C1[C@@H](CC(=O)O)CN)Cl |
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| InChi Key | KPYSYYIEGFHWSV-QMMMGPOBSA-N | |
| InChi Code | InChI=1S/C10H12ClNO2/c11-9-3-1-7(2-4-9)8(6-12)5-10(13)14/h1-4,8H,5-6,12H2,(H,13,14)/t8-/m0/s1 | |
| Chemical Name | (3R)-4-amino-3-(4-chlorophenyl)butanoic acid | |
| Synonyms |
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| 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 |
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| 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 |
GABAB receptors (Ki = 1.2 μM for rat brain membrane preparations) [2] - GABAA receptors (weak affinity, Ki > 100 μM for rat brain membrane preparations) [2] |
| ln Vitro |
In vitro activity: Baclofen is a skeletal muscle relaxant used in the treatment of spasticity of spinal and cerebral origin. Although it is marketed as a racemic mixture, only the baclofen R-enantiomer is stereospecifically active at so called GAGAB-receptors. Researchers believe that the enantiomers of baclofen have different properties. It is claimed that the R-(−)-enantiomer is about 100 times more active than the S-(+)-enantiomer. (R)-baclofen showed high affinity for GABAB receptors in rat brain membrane preparations, with a Ki value of 1.2 μM, while its affinity for GABAA receptors was negligible (Ki > 100 μM) [2] - (R)-baclofen did not affect GABA uptake in rat brain membrane preparations at concentrations up to 100 μM, indicating no interaction with GABA transporters [2] |
| ln Vivo |
At an effective dose of 1 mg/kg, (R)-Baclofen (STX209) reduces audiogenic seizures in Fmr1-knockout mice on a seizure-resistant C57BL/6 background [5]. With a minimum effective dosage (MED) of 1.5 mg/kg, acute intraperitoneal administration of (R)-Baclofen (STX209) considerably decreased the percentage of mice having seizures (seizure incidence) [5]. Intrathecal administration of (R)-baclofen (1–10 μg/rat) in rats induced dose-dependent cardiovascular responses, including a decrease in mean arterial blood pressure (maximal reduction of 28.3% ± 3.2% at 10 μg) and a slowing of heart rate (maximal reduction of 19.6% ± 2.7% at 10 μg). These effects were completely antagonized by the GABAB receptor antagonist phaclofen (20 μg/rat, intrathecal) [1] - In spastic multiple sclerosis patients, intravenous administration of (R)-baclofen (50 μg) significantly inhibited transmission in spinal pathways. The amplitude of motor evoked potentials (MEPs) recorded from the abductor pollicis brevis muscle was reduced by 35.7% ± 4.8% compared to baseline, and the central motor conduction time was prolonged by 12.3% ± 2.1% [4] |
| Enzyme Assay |
Rat brain membrane preparations were prepared by homogenizing brain tissues in ice-cold buffer, followed by centrifugation to obtain crude membrane fractions. Membranes were incubated with tritiated GABA (for GABAB receptor binding) or tritiated muscimol (for GABAA receptor binding) in the presence of increasing concentrations of (R)-baclofen (0.1–100 μM) at 4°C for 60 minutes. Unbound ligands were removed by rapid filtration through glass fiber filters, and the radioactivity of bound ligands was measured by liquid scintillation counting to calculate Ki values [2] - For GABA uptake assays, rat brain membrane preparations were incubated with tritiated GABA and (R)-baclofen (0.1–100 μM) at 37°C for 10 minutes. The reaction was terminated by adding ice-cold buffer, and the mixture was filtered. Radioactivity of the filtered membranes was counted to assess the effect of (R)-baclofen on GABA uptake [2] |
| Animal Protocol |
1, 1.5 mg/kg; i.p. Mice Male Wistar rats (250–300 g) were anesthetized and implanted with an intrathecal catheter targeting the lumbar spinal cord. After a 3-day recovery period, (R)-baclofen was dissolved in sterile saline and administered intrathecally at doses of 1, 3, 10 μg/rat. Phaclofen was administered intrathecally 10 minutes before (R)-baclofen in antagonism experiments. Mean arterial blood pressure and heart rate were recorded continuously for 60 minutes after drug administration using a femoral artery catheter connected to a pressure transducer [1] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Unlike baclofen, absorption of arbaclofen is not limited to the upper small intestine. Arbaclofen can also be absorbed in the lower small intestine and the colon, allowing for the development of sustained release formulations. >80% of R-baclofen is renally eliminated unchanged. Blood clearance of an IV bolus of R-baclofen in rats, monkeys, and dogs, resulted in a half life of 1.6-3.4hours, in one study. Total blood clearance was reported to be 0.51±0.13L/h/kg in rats, 0.31±0.11L/h/kg in monkeys, and 0.24±0.01L/h/kg in dogs. (2) |
| References |
[1]. Effects of phaclofen and the enantiomers of baclofen on cardiovascular responses to intrathecal administration of L- and D-baclofen in the rat. Eur J Pharmacol. 1991 Apr 24;196(3):267-75. [2]. Comparative stereostructure-activity studies on GABAA and GABAB receptor sites and GABA uptake using rat brain membrane preparations. J Neurochem. 1986 Sep;47(3):898-903. [3]. Comparative stereostructure-activity studies on GABAA and GABAB receptor sites and GABA uptake using rat brain membrane preparations. J Neurochem. 1986 Sep;47(3):898-903. [4]. The effect of baclofen on the transmission in spinal pathways in spastic multiple sclerosis patients. Clin Neurophysiol. 2000 Aug;111(8):1372-9. |
| Additional Infomation |
Arbaclofen is an organooxygen compound and an organonitrogen compound. It is functionally related to a gamma-amino acid. Arbaclofen, or STX209, is the R-enantiomer of baclofen. It is believed to be a selective gamma-amino butyric acid type B receptor agonist, and has been investigated as a treatment for autism spectrum disorder and fragile X syndrome in randomized, double blind, placebo controlled trials. It has also been investigated as a treatment for spasticity due to multiple sclerosis and spinal cord injury. Arbaclofen was investigated as a treatment for gastroesophageal reflux disease (GERD); however, with disappointing results. Drug Indication Investigated in clinical trials as a potential treatment for spasticity in multiple sclerosis, autism spectrum disorder, and social withdrawal in fragile X syndrome. Mechanism of Action Arbaclofen, or R-baclofen, acts upstream of the mGluR5 receptor to increase inhibitory neurotransmission. It is the isomer of baclofen which harbors antispastic activity. (R)-baclofen (STX209) is the biologically active enantiomer of baclofen, acting as a selective GABAB receptor agonist [2] - The cardiovascular effects of intrathecal (R)-baclofen in rats are mediated exclusively via spinal GABAB receptors, as demonstrated by complete antagonism by phaclofen [1] - In spastic multiple sclerosis patients, (R)-baclofen inhibits spinal motor pathway transmission, which may underlie its clinical efficacy in reducing spasticity [4] - (R)-baclofen shows significant stereoselectivity in GABAB receptor binding, with the (S)-enantiomer exhibiting negligible affinity (Ki > 100 μM) for GABAB receptors [2] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 4.17 mg/mL (19.52 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C). (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.6803 mL | 23.4017 mL | 46.8033 mL | |
| 5 mM | 0.9361 mL | 4.6803 mL | 9.3607 mL | |
| 10 mM | 0.4680 mL | 2.3402 mL | 4.6803 mL |