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| Targets |
Ki: 8.6 nM (κ-opioid receptor in guinea pig), 252 nM (μ-receptor) and 9400 nM (δ-receptor)[2]
kappa-opioid receptor (KOR). Spiradoline mesylate is a selective KOR agonist with a Ki of 8.6 nM in guinea pig brain. It has significantly lower affinity for micro-opioid receptor (Ki = 252 nM) and delta-opioid receptor (Ki = 9400 nM), demonstrating functional selectivity for KOR. |
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| ln Vitro |
Employing the patch-clamp technique on isolated rat heart myocytes, it was found that spirolline mesylate (15 to 500 μM) inhibits potassium currents and sodium channels in cardiac tissue to create its antiarrhythmmic effect. At higher dosages, it also blocks potassium channels. Consequently, spirolidine mesylate decreases the sustained plateau potassium amplitude, decreases the peak sodium current, and speeds up the transient outward potassium current's decay rate[2].
Spiradoline mesylate binds to KOR with Ki = 8.6 nM, with lower affinity for micro (Ki = 252 nM) and negligible affinity for delta (Ki = 9400 nM). Using the patch-clamp method on rat isolated cardiomyocytes, spiradoline mesylate (15-500 microM) exerts antiarrhythmic effects by blocking sodium channels (and also blocking potassium currents at higher doses), decreasing peak sodium current, accelerating decay of transient outward potassium current, and reducing sustained plateau potassium amplitude. |
| ln Vivo |
In non-stressed adults, spiradoline mesylate (U-62066; 0.1-0.4 mg/kg; subcutaneous injection; once; Sprague-Dawley rats) treatment dose-dependently reduces social behaviors, resulting in social avoidance at the highest dose tested. However, younger animals show reduced sensitivity to this socially suppressing effect of spiradoline mesylate. The Spiradoline mesylate's socially suppressive effects are decreased in stressed animals at all ages, with juveniles and adolescents displaying greater social preference in response to specific dosages of U-62066[1].
Spiradoline mesylate has potent diuretic, analgesic, antiarrhythmic, antitussive, and neuroprotective activities. It easily penetrates the BBB. It was designed to provide potent analgesia without the mu-opioid receptor-mediated adverse effects of morphine, including physical dependence and respiratory depression. In vivo efficacy studies have demonstrated its analgesic, diuretic, and antiarrhythmic effects in rodents. |
| Enzyme Assay |
Cell-free kappa-opioid receptor binding assays are performed using guinea pig brain membranes. Membranes are incubated with 0.5-2 nM [3H]-U69,593 (a selective KOR radioligand) or [3H]-bremazocine (non-selective) in the presence of appropriate blockers, and increasing concentrations of spiradoline mesylate (0.001-10,000 nM) in 50 mM Tris-HCl (pH 7.4) containing 1 mM EDTA and 0.1% BSA for 60-90 min at 25degC. Bound radioactivity is separated by GF/B filtration. Ki values are calculated by nonlinear regression using the Cheng-Prusoff equation. Ki(KOR) = 8.6 nM; Ki(MOR) = 252 nM; Ki(DOR) = 9400 nM. For micro and delta assays, guinea pig brain membranes are incubated with [3H]-DAMGO and [3H]-DPDPE, respectively.
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| Cell Assay |
Functional activity assays: CHO-K1 cells stably expressing human kappa-opioid receptors are loaded with a cAMP detection kit (HTRF). Spiradoline mesylate is added at increasing concentrations (0.01-10,000 nM), and inhibition of forskolin-stimulated cAMP accumulation is measured. The EC50 for KOR activation is determined from dose-response curves. Spiradoline mesylate acts as a full agonist at KOR, potently inhibiting adenylyl cyclase. For selectivity confirmation, similar assays are performed using cells expressing micro and delta receptors; spiradoline mesylate shows much lower potency at these subtypes. For cardiac electrophysiology: rat isolated cardiomyocytes are subjected to whole-cell patch-clamp recording. Spiradoline mesylate (15-500 microM) is applied to the bath solution, and sodium currents (INa), transient outward potassium currents (Ito), and sustained potassium currents are recorded.
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| Animal Protocol |
Animal/Disease Models: Juvenile, adolescent and adult SD (Sprague-Dawley) male and female rats exposed to repeated restraint[1]
Doses: 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, and 0.4 mg/kg Route of Administration: subcutaneous (sc) injection; once Experimental Results: Dose-dependently decreased social behaviors in non-stressed adults, producing social avoidance at the highest dose tested. Diuretic and analgesic effects: Male Sprague-Dawley rats receive spiradoline mesylate s.c. (0.1-10 mg/kg). Urine output is measured for 4 hours. Diuretic effect is dose-dependent, mediated by KOR activation in the kidney. Analgesia is assessed by the tail-flick test (55degC) and hot-plate test at 15-60 min post-injection. Analgesia is KOR-mediated and can be reversed by the KOR antagonist norbinaltorphimine. For antiarrhythmic evaluation: rat models of arrhythmia (e.g., ischemia/reperfusion) are used; electrocardiograms are recorded. For pharmacokinetic studies, spiradoline mesylate (10 mg/kg) is administered to rats s.c. or i.v. Blood samples are collected at 0-12 hours, and plasma concentrations are analyzed by LC-MS/MS to determine t1/2, Cmax, AUC, and clearance. |
| ADME/Pharmacokinetics |
Spiradoline mesylate has a molecular weight of 449.0 (C22H30Cl2N2O·CH4O3S). It easily penetrates the BBB, allowing central KOR engagement after peripheral administration. Half-life in rodents is moderate (approximately 1-3 hours). Oral bioavailability is moderate (not fully characterized). Storage: -20degC, protected from light. Solubility: DMSO and water. Spiradoline is metabolized primarily by CYP3A4 in human liver microsomes.
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| Toxicity/Toxicokinetics |
In preclinical toxicology studies, spiradoline mesylate was generally well-tolerated at analgesic doses, but KOR agonists are known to produce dose-dependent diuresis, sedation, dysphoria, and psychotomimetic effects in humans. Spiradoline may cause CNS depression and mild respiratory depression (less than morphine). It did not produce mu-mediated euphoria or physical dependence in animal studies. However, clinical development was discontinued due to these KOR-mediated side effects (sedation, dysphoria, diuresis). No FDA approval.
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| References |
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| Additional Infomation |
See also: Morphine Sulfate (related); Spiradoline (has active moiety).
Other information: Spiradoline mesylate (U-62066 mesylate) is a research compound, not FDA-approved. CAS# 87173-97-5. It was developed by Upjohn (Pharmacia) as a selective KOR agonist for the treatment of pain. It has also been studied for diuretic and antiarrhythmic applications. Due to its potential for dysphoric and psychotomimetic effects (hallucinations, depersonalization), it never reached clinical approval. It remains a valuable research tool for studying KOR pharmacology, including analgesia, diuresis, and receptor-mediated signaling pathways. For research use only. |
| Molecular Formula |
C23H34CL2N2O5S
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|---|---|
| Molecular Weight |
521.50
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| Exact Mass |
520.156
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| CAS # |
87173-97-5
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| Related CAS # |
Spiradoline;87151-85-7
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| PubChem CID |
55651
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
33
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| Complexity |
649
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| Defined Atom Stereocenter Count |
3
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| SMILES |
CN([C@H]1CC[C@@]2(CCCO2)C[C@@H]1N3CCCC3)C(=O)CC4=CC(=C(C=C4)Cl)Cl.CS(=O)(=O)O
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| InChi Key |
FHEZDPDAYTVKKG-JLBKCEDKSA-N
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| InChi Code |
InChI=1S/C22H30Cl2N2O2.CH4O3S/c1-25(21(27)14-16-5-6-17(23)18(24)13-16)19-7-9-22(8-4-12-28-22)15-20(19)26-10-2-3-11-26;1-5(2,3)4/h5-6,13,19-20H,2-4,7-12,14-15H2,1H3;1H3,(H,2,3,4)/t19-,20-,22-;/m0./s1
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| Chemical Name |
2-(3,4-dichlorophenyl)-N-methyl-N-[(5R,7S,8S)-7-pyrrolidin-1-yl-1-oxaspiro[4.5]decan-8-yl]acetamide;methanesulfonic acid
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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 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)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9175 mL | 9.5877 mL | 19.1755 mL | |
| 5 mM | 0.3835 mL | 1.9175 mL | 3.8351 mL | |
| 10 mM | 0.1918 mL | 0.9588 mL | 1.9175 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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