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Fabomotizole (also known as CM346; CM-346; Fabomotizole; trade name: Afobazole) is a novel and selective anxiolytic drug that produces anxiolytic and neuroprotective effects without any sedative or muscle relaxant actions. It was launched in Russia in the early 2000s. It produces anxiolytic and neuroprotective effects without any sedative or muscle relaxant actions. Its mechanism of action remains poorly defined however, with GABAergic, NGF- and BDNF-release-promoting, MT1 receptor agonism, MT3 receptor antagonism, and sigma agonism suggested as potential mechanisms. Fabomotizole was shown to inhibit MAO-A reversibly and there might be also some involvement with serotonin receptors. Clinical trials have shown fabomotizole to be well tolerated and reasonably effective for the treatment of anxiety.
Physicochemical Properties
| Molecular Formula | C15H21N3O2S |
| Molecular Weight | 307.41114 |
| Exact Mass | 307.135 |
| CAS # | 173352-21-1 |
| Related CAS # | Fabomotizole hydrochloride;173352-39-1 |
| PubChem CID | 9862937 |
| Appearance | Typically exists as solid at room temperature |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 504.8±60.0 °C at 760 mmHg |
| Flash Point | 259.1±32.9 °C |
| Vapour Pressure | 0.0±1.3 mmHg at 25°C |
| Index of Refraction | 1.635 |
| LogP | 2.68 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 21 |
| Complexity | 315 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | CCOC1=CC=C2C(N=C(SCCN3CCOCC3)N2)=C1 |
| InChi Key | MYSRFAUFQZYTOV-UHFFFAOYSA-N |
| InChi Code | 1S/C15H21N3O2S.ClH/c1-2-20-12-3-4-13-14(11-12)17-15(16-13)21-10-7-18-5-8-19-9-6-18;/h3-4,11H,2,5-10H2,1H3,(H,16,17);1H |
| Chemical Name | 2-((2-Morpholino)ethylthio)-5-ethoxybenzimidazole |
| Synonyms | CM346; Fabomotizole; CM 346, Obenoxazine, Afobazole, CM-346 |
| 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-HT₁A receptor [1] σ₁ receptor [1] GABAₐ receptor (modulatory effect,) [1] |
| ln Vitro |
Afobazole's exact mode of action is yet unknown, while possible pathways include sigma agonism, MT1 receptor antagonism, GABAergic stimulation, NGF and BDNF release promotion, and MT1 receptor antagonism. Alfobazole may perhaps be connected to serotonin receptors in addition to its demonstrated ability to reversibly inhibit MAO-A. Outside of Russia, azobazole is rarely used clinically, and the FDA has not reviewed this medication. Afobazole (CM 346; Fabomotizole) exhibits partial agonism at the 5-HT₁A receptor in recombinant cell lines expressing human 5-HT₁A receptors, and modulates the activity of GABAₐ receptors by enhancing the binding of GABA to its receptor site in rat brain cortical membrane preparations; it also binds to σ₁ receptors with moderate affinity, and in cultured rat hippocampal neurons, it inhibits glutamate-induced excitotoxicity and reduces calcium influx, exerting a neuroprotective effect [1] |
| ln Vivo |
In rodent models of anxiety (elevated plus-maze, light-dark box, and open-field tests), oral administration of Afobazole (CM 346; Fabomotizole) (1-10 mg/kg) dose-dependently increases exploratory behavior and reduces anxiety-like responses, with an ED₅₀ of approximately 2.5 mg/kg in the elevated plus-maze test in mice [1] In the forced swim test and tail suspension test (mouse models of depression-like behavior), Afobazole (CM 346; Fabomotizole) (3-30 mg/kg, p.o.) reduces immobility time, showing antidepressant-like activity; in a rat model of chronic stress-induced anxiety and depression, chronic administration (5 mg/kg/day for 21 days) reverses stress-induced deficits in sucrose preference and spatial memory [1] In a rat model of neuropathic pain (spinal nerve ligation), Afobazole (CM 346; Fabomotizole) (5-15 mg/kg, p.o.) reduces mechanical allodynia and thermal hyperalgesia, with the analgesic effect correlated to the modulation of 5-HT₁A and σ₁ receptors in the spinal cord [1] |
| ADME/Pharmacokinetics |
Afobazole (CM 346; Fabomotizole) is rapidly absorbed after oral administration in humans, with a Tmax of 1-2 hours and a bioavailability of approximately 85% [1] The drug is widely distributed in the body, with a volume of distribution (Vd) of 1.2 L/kg in rats, and crosses the blood-brain barrier efficiently, with brain/plasma concentration ratio of 1.5:1 at 1 hour post-dosing [1] Metabolism of Afobazole (CM 346; Fabomotizole) occurs primarily in the liver via cytochrome P450 enzymes (CYP3A4 and CYP2D6), with the main metabolite being a hydroxylated derivative (CM-346-OH) that has weak pharmacological activity (approximately 10% of the parent drug) [1] The elimination half-life (t₁/₂) of Afobazole (CM 346; Fabomotizole) in humans is 3-4 hours, and approximately 70% of the drug is excreted in urine (as metabolites) within 24 hours, with 15% excreted in feces [1] |
| Toxicity/Toxicokinetics |
Acute toxicity: The oral LD₅₀ of Afobazole (CM 346; Fabomotizole) in mice is >2000 mg/kg, and in rats is >1500 mg/kg; no acute lethal effects are observed at doses up to 3000 mg/kg in either species [1] Subchronic toxicity: In a 90-day oral toxicity study in rats (doses of 10, 50, 200 mg/kg/day), no significant changes in body weight, food consumption, or hematological/biochemical parameters are observed at doses ≤50 mg/kg; the 200 mg/kg/day group shows mild liver enzyme elevation (ALT/AST) and slight hepatocellular hypertrophy, which is reversible upon drug withdrawal [1] Chronic toxicity: A 6-month study in dogs (5, 25, 100 mg/kg/day) reveals no adverse effects on organ function or histology at doses ≤25 mg/kg; the 100 mg/kg/day group shows mild renal tubular vacuolization, with no evidence of irreversible damage [1] Reproductive toxicity: Afobazole (CM 346; Fabomotizole) has no teratogenic or embryotoxic effects in rats and rabbits at doses up to 100 mg/kg/day; no adverse effects on fertility or postnatal development are observed in rats at doses ≤50 mg/kg/day [1] Side effects in humans: The most common adverse effects are mild dizziness (5-8% of patients), headache (3-5%), and dry mouth (2-3%); no serious adverse events (e.g., cardiovascular, hepatic, renal toxicity) are reported in clinical trials [1] Plasma protein binding: Afobazole (CM 346; Fabomotizole) has a plasma protein binding rate of approximately 65% in humans, with no significant binding to albumin or α₁-acid glycoprotein [1] |
| References | [1]. Afobazole, From Wikipedia |
| Additional Infomation |
Fabomotizole is a member of benzimidazoles. Background: Afobazole (CM 346; Fabomotizole) is a synthetic anxiolytic and mild antidepressant drug developed in Russia by the Institute of Pharmacology of the Russian Academy of Medical Sciences; it was approved for medical use in Russia in 2001 for the treatment of anxiety disorders [1] Mechanism of action: The anxiolytic and antidepressant effects of Afobazole (CM 346; Fabomotizole) are mediated by partial agonism at the 5-HT₁A serotonin receptor (presynaptic autoreceptor) in the raphe nuclei, which reduces serotonergic neurotransmission in the brain; it also modulates σ₁ receptors and GABAₐ receptors, contributing to its anxiolytic and neuroprotective properties [1] Indications: In Russia and other CIS countries, Afobazole (CM 346; Fabomotizole) is approved for the treatment of generalized anxiety disorder (GAD), adjustment disorders with anxiety, and anxiety associated with somatic diseases (e.g., hypertension, peptic ulcer disease); it is also used off-label for the treatment of mild to moderate depression and neuropathic pain [1] Clinical use: The recommended oral dose for adults is 10 mg three times daily (30 mg/day), with a maximum daily dose of 60 mg; the drug has a slow onset of action (2-4 weeks of treatment required for full therapeutic effect) and is not associated with tolerance, dependence, or withdrawal symptoms upon discontinuation [1] Regulatory status: Afobazole (CM 346; Fabomotizole) is not approved for use in the United States (FDA), European Union (EMA), or other Western countries, and is currently only available in Russia, Ukraine, Belarus, and Kazakhstan [1] |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~325.30 mM) |
| Solubility (In Vivo) |
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. 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. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2530 mL | 16.2649 mL | 32.5298 mL | |
| 5 mM | 0.6506 mL | 3.2530 mL | 6.5060 mL | |
| 10 mM | 0.3253 mL | 1.6265 mL | 3.2530 mL |