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| Targets |
Espindolol targets β1, β2, and β3 adrenergic receptors, acting as a non-selective β-adrenoceptor antagonist with intrinsic sympathomimetic activity (ISA). It also targets the 5-HT1A serotonin receptor, acting as an agonist. This dual mechanism distinguishes Espindolol from other β-blockers and may contribute to its effects on heart rate, cardiac output, and metabolism.
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| ln Vitro |
l-Pindolol (1 nM-100 μM) reduces the supermaximal CA1 pyramidal cells caused by 100 nM 5-CT with an IC50 value of 92 nM [1]. l-Pindolol (500 nM and 1 μM) blocks 5-toluidine tryptamine (5-CT; 10 nM) and 5-hydroxyamine tryptamine (5-HT; 15 μM) by detecting 5-CT and 5-HT on CA1 pyramidal cells. With an IC50 value of 522 nM, l-Pindolol (1 nM-100 μM) suppresses the supraminimal proliferation of CA3 neurons generated by 300 nM 5-CT[1].
In vitro, Espindolol acts as a non-selective β-adrenoceptor antagonist with intrinsic sympathomimetic activity. It also activates 5-HT1A receptors. The compound modulates adrenergic and serotonergic signaling pathways. Specific IC50 or EC50 values for receptor binding and activation are available from pharmacological studies. |
| ln Vivo |
In brain regions where 5-HT1A receptors are present, [3H]-WAY 100635 accumulation was decreased by l-pindolol (15 mg/kg; i.p., repaired prior to [3H]-WAY 100635 injection).
In vivo, Espindolol has been investigated for the treatment of heart failure and cachexia. Its β-blockade with ISA reduces heart rate and cardiac workload while maintaining some sympathetic tone. The 5-HT1A agonism may contribute to metabolic effects and appetite regulation. Espindolol has shown efficacy in improving symptoms and outcomes in preclinical and clinical studies. |
| Enzyme Assay |
The in vitro receptor binding assay for Espindolol involves measuring its affinity for β1, β2, β3 adrenergic receptors and 5-HT1A serotonin receptors. Radiolabeled ligand binding assays are performed using membrane preparations from cells expressing these receptors. Varying concentrations of Espindolol are incubated with the receptor preparation, and binding affinity (IC50 or Ki) is determined. The compound's intrinsic sympathomimetic activity is assessed by measuring cAMP accumulation.
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| Cell Assay |
In vitro cellular assays for Espindolol involve treating cultured cardiomyocytes or neuronal cells with varying concentrations of the compound. β-adrenoceptor activation is assessed by measuring cAMP levels. 5-HT1A receptor activation is assessed by measuring downstream signaling. The compound's effects on cell viability, contractility, and metabolic parameters are evaluated.
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| Animal Protocol |
Animal/Disease Models: Male Sprague Dawley rat [1]
Doses: 15 mg/kg Route of Administration: intraperitoneal (ip) injection; [3H]-WAY 100635 15 mg/kg before injection, 20 minutes acute treatment or 24 hrs (hrs (hours)), 16 hrs (hrs (hours)) and 20 minutes Short-term treatment Experimental Results: [3H]-WAY 100635 accumulation was diminished in brain regions containing 5-HT1A receptors, but had no effect on the dorsal raphe nucleus (DRN), hippocampal CA1 and CA3 regions. In vivo animal experiments for Espindolol typically use rodent models of heart failure or cachexia. The compound is administered orally at various doses. Cardiac function is assessed by echocardiography. Body weight, food intake, and metabolic parameters are monitored. The compound's effects on survival, cardiac remodeling, and cachexia are evaluated. Specific protocols are available from preclinical studies. |
| ADME/Pharmacokinetics |
Espindolol has been characterized in preclinical pharmacokinetic studies. As a small molecule β-blocker with 5-HT1A agonism, it is expected to have oral bioavailability and reasonable tissue distribution. The compound has a molecular weight of 248.32 (C15H20N2O2). Specific PK parameters including half-life, Cmax, and metabolic pathways are available from preclinical studies.
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| Toxicity/Toxicokinetics |
Espindolol has been evaluated in clinical trials for heart failure and cachexia. As a β-blocker, potential adverse effects may include bradycardia, hypotension, and fatigue. The compound's ISA may reduce the risk of excessive bradycardia. The 5-HT1A agonism may contribute to gastrointestinal effects. Complete toxicology data are available from the compound's clinical development program.
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| References |
J Cachexia Sarcopenia Muscle. 2014 Jun;5(2):149-58.
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| Additional Infomation |
(S)-(-)-indolol is an indolol. It is the enantiomer of (R)-(+)-indolol.
Espindolol (CAS#: 26328-11-0) is a non-selective β-adrenoceptor antagonist with intrinsic sympathomimetic activity (ISA) and 5-HT1A receptor agonism, also known as AGI-001. It has been investigated for the treatment of heart failure and cachexia. Espindolol's unique dual mechanism distinguishes it from other β-blockers. The compound is not approved for clinical use and remains an investigational agent. |
| Molecular Formula |
C14H20N2O2
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|---|---|
| Molecular Weight |
248.32
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| Exact Mass |
248.152
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| CAS # |
26328-11-0
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| PubChem CID |
688095
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| Appearance |
Light brown to gray solid powder
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| Density |
1.152g/cm3
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| Boiling Point |
457.1ºC at 760mmHg
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| Vapour Pressure |
3.77E-09mmHg at 25°C
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| Index of Refraction |
1.596
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| LogP |
2.296
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
18
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| Complexity |
248
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC(C)NC[C@@H](COC1=CC=CC2=C1C=CN2)O
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| InChi Key |
JZQKKSLKJUAGIC-NSHDSACASA-N
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| InChi Code |
InChI=1S/C14H20N2O2/c1-10(2)16-8-11(17)9-18-14-5-3-4-13-12(14)6-7-15-13/h3-7,10-11,15-17H,8-9H2,1-2H3/t11-/m0/s1
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| Chemical Name |
(2S)-1-(1H-indol-4-yloxy)-3-(propan-2-ylamino)propan-2-ol
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| Synonyms |
AGI001 MT-102 Synonym
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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 |
| 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 : ~100 mg/mL (~402.71 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (10.07 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 (10.07 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.0271 mL | 20.1353 mL | 40.2706 mL | |
| 5 mM | 0.8054 mL | 4.0271 mL | 8.0541 mL | |
| 10 mM | 0.4027 mL | 2.0135 mL | 4.0271 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.
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