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Purity: ≥98%
Pirmenol (Cl-845) is a potent antiarrhythmic agent that inhibits muscarinic acetylcholine receptor-operated K+ current in the guinea pig heart. Pirmenol has an IC50 of 0.1 μM for inhibiting Carbachol-induced IK.ACh. Pirmenol has a favorable therapeutic index when compared to other class I agents and is active in a variety of experimental arrhythmic models with different etiologies. Pirmenol has a high degree of effectiveness regardless of the type of arrhythmia—atrial, ventricular, chemically, mechanically, electrically, or reentrant.
| Targets |
IK.ACh ( IC50 = 0.1 μM )
Muscarinic acetylcholine receptors (mediating the muscarinic acetylcholine receptor-operated K+ current, I_K.ACh; no IC50, Ki, or EC50 values provided) [1] - Calcium channels, delayed outward potassium channels (influencing cardiac action potentials; no IC50, Ki, or EC50 values provided); muscarinic acetylcholine receptors [3] |
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| ln Vitro |
Pirmenol (1 μM) inhibits the intracellular loading of GTPg S in atrial cells or IK.ACh induced by carbachol[1].
Pirmenol (5 μM) prolongs the final repolarization of the action potentials and depresses the early portion of the plateau in ventricular myocytes[3]. Pirmenol (1 μM) increases the action potential duration at 90% repolarization in atrial muscles and Purkinje fibers[3]. 1. In isolated atrial myocytes from guinea pigs, pirmenol concentration-dependently inhibited the muscarinic acetylcholine receptor-operated K+ current (I_K.ACh) induced by carbachol or intracellular loading of GTPγS. Its inhibitory effect on carbachol-induced I_K.ACh was more potent than that on GTPγS-induced I_K.ACh [1] 2. In multicellular cardiac preparations (atrial muscles, Purkinje fibers, papillary muscles) and ventricular myocytes from rabbits and guinea pigs: - At concentrations of 5 μM and higher, pirmenol suppressed sinus node automaticity by depressing slow diastolic depolarization without altering the maximum diastolic potential [3] - At concentrations of 1 μM and higher, pirmenol depressed the maximum upstroke velocity (Vmax) of action potentials and prolonged the action potential duration at 90% repolarization (APD90) in atrial muscles and Purkinje fibers, with no effect on resting membrane potentials [3] - At a concentration of 5 μM, pirmenol depressed the early part of the plateau and lengthened the final repolarization of action potentials in ventricular myocytes, which was attributed to the inhibition of calcium current and delayed outward K+ current [3] - At concentrations of 1-5 μM, pirmenol markedly inhibited triggered tachyarrhythmias arising from delayed afterdepolarizations (DADs) in papillary muscles and ventricular myocytes, and altered the amplitude and appearance of the transient inward current in ventricular myocytes [3] |
| ln Vivo |
Pirmenol (2.5 and 5 mg/kg, p.o.) is effective against arrhythmias in conscious, coronary artery ligated dogs[4]. Rats exposed to pirmenol had LD50s of 23.6 mg/kg intravenously and 359.9 mg/kg po[2]. Mice exposed to pirmenol had LD50s of 20.8 mg/kg intravenously and 215.5 mg/kg po[2].
1. In Langendorff-perfused isolated guinea pig hearts, pirmenol reversed the carbachol-induced decreases in effective refractory periods (ERP) and atrial fibrillation threshold [1] 2. In conscious dogs with coronary artery ligation (arrhythmia model): - pirmenol (administered via intravenous, intramuscular, and oral routes) effectively restored normal sinus rhythm. A dose of 2.5 mg/kg was effective against arrhythmias occurring on the second day after ligation, while 5 mg/kg was effective against the higher-rate arrhythmias on the first day after ligation [4] - Slow intravenous infusion of pirmenol at 1-2 mg/kg/hr maintained nearly complete arrhythmia conversion in dogs with first-day post-ligation arrhythmias [4] - Rapid intravenous infusion at 10 mg/kg/hr showed a good correlation between dose, plasma level, and arrhythmia conversion. Mean conversion to 80% normal rhythm was achieved at 2.5 mg/kg (associated plasma level: 0.8 ± 0.1 μM/ml), while the first signs of gross toxicity occurred at 21.7 ± 2.4 mg/kg (associated plasma level: 6.2 ± 0.4 μM/ml). Even at large doses, pirmenol had minimal effects on cardiac conduction and blood pressure [4] - pirmenol was safe and effective when combined with other antiarrhythmic agents (disopyramide, lidocaine, procainamide, propranolol, quinidine) [4] |
| Cell Assay |
1. Atrial myocyte assay (guinea pig): Isolated atrial myocytes from guinea pigs were prepared, and the patch-clamp technique was used to record the muscarinic acetylcholine receptor-operated K+ current (I_K.ACh). The current was induced by either carbachol treatment or intracellular loading of GTPγS, and the concentration-dependent inhibitory effects of pirmenol on I_K.ACh were measured and compared between the two induction methods [1]
2. Cardiomyocyte and multicellular preparation assays (rabbit and guinea pig): - Ventricular myocytes were isolated from rabbits and guinea pigs, and the suction-pipette whole-cell clamp method was applied to record action potentials, calcium current, delayed outward K+ current, and transient inward current. The effects of pirmenol (at different concentrations) on the shape, duration, and related ion currents of ventricular myocyte action potentials were analyzed [3] - Multicellular preparations (atrial muscles, Purkinje fibers, papillary muscles) were obtained from rabbit and guinea pig hearts, and the microelectrode technique was used to record parameters such as maximum upstroke velocity (Vmax) of action potentials, action potential duration at 90% repolarization (APD90), and resting membrane potential. The effects of pirmenol on these electrophysiological parameters and on delayed afterdepolarization (DAD)-induced triggered tachyarrhythmias in papillary muscles were evaluated [3] |
| Animal Protocol |
Conscious, coronary artery ligated dogs
Oral administration (p.o.) 2.5 and 5 mg/kg 1. Langendorff-perfused guinea pig heart assay: Isolated guinea pig hearts were mounted on a Langendorff perfusion system. First, carbachol was administered to induce decreases in effective refractory periods (ERP) and atrial fibrillation threshold. Then, pirmenol was administered via the perfusion system, and changes in ERP and atrial fibrillation threshold were monitored to assess the effect of pirmenol [1] 2. Coronary artery-ligated conscious dog assay (arrhythmia model): - Dogs were subjected to coronary artery ligation to establish an arrhythmia model. After model establishment, pirmenol was administered via three routes: intravenous injection, intramuscular injection, and oral gavage. Doses of 2.5 mg/kg and 5 mg/kg were used to evaluate efficacy against arrhythmias on the second and first days post-ligation, respectively [4] - For intravenous infusion experiments: pirmenol was infused at a slow rate of 1-2 mg/kg/hr to maintain arrhythmia conversion, and at a rapid rate of 10 mg/kg/hr to analyze the correlation between dose, plasma concentration, arrhythmia conversion rate, and toxicity. Plasma concentrations of pirmenol were measured at different time points, and cardiac conduction and blood pressure were monitored throughout the experiment [4] - For drug interaction experiments: pirmenol was co-administered with other antiarrhythmic agents (disopyramide, lidocaine, procainamide, propranolol, quinidine) via appropriate routes. The safety and efficacy of the combinations in restoring normal sinus rhythm were evaluated [4] 3. Preclinical toxicology animal assays: Animals including mice, rats, rabbits, and dogs were used. pirmenol hydrochloride (CI-845) was administered via oral and intravenous routes. General toxic reactions of the animals were observed, but specific dose frequencies and detailed observation indicators were not provided [2] |
| ADME/Pharmacokinetics |
In conscious dogs with coronary artery ligation, the plasma concentration required to restore normal heart rhythm in 80% of dogs with rapid intravenous infusion of pimecrolimus (10 mg/kg/hr) was 0.8 ± 0.1 μM/ml (dose 2.5 mg/kg), and the plasma concentration at which significant toxicity symptoms were observed was 6.2 ± 0.4 μM/ml (dose 21.7 ± 2.4 mg/kg) [4]
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| Toxicity/Toxicokinetics |
1. Preclinical toxicology studies: Oral and intravenous administration of pimecrolimus hydrochloride was conducted in mice, rats, rabbits and dogs. [2] 2. In conscious dogs with coronary artery ligation: Even at high doses of pimecrolimus, the effects on cardiac conduction and blood pressure were minimal. The initial dose at which significant toxic symptoms appeared during rapid intravenous infusion (10 mg/kg/hr) was 21.7 ± 2.4 mg/kg (relevant plasma concentration: 6.2 ± 0.4 μM/ml) [4]
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| References |
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| Additional Infomation |
Piromeno is a racemic mixture. 1. Piromeno mainly inhibits muscarinic acetylcholine receptor-mediated K+ currents (I_K.ACh) by blocking muscarinic receptors, which may help prevent vagal-induced atrial fibrillation [1]. 2. Piromeno has electrophysiological properties that help it exert antiarrhythmic effects on various types of arrhythmias, including arrhythmias associated with sinoatrial node automaticity, action potential parameters, and delayed depolarization-induced triggered tachyarrhythmias [3]. 3. Piromeno hydrochloride (CI-845) is an orally effective long-acting antiarrhythmic drug. In canine models of coronary artery ligation, this drug showed higher efficacy, longer duration of action, and/or a wider safety profile compared to reference antiarrhythmic drugs (azimarin, apralindine, disopyramide, lidocaine, mexiletine, procainamide, quinidine) [4]. 4. Pirometrozine hydrochloride (CI-845) is a novel antiarrhythmic drug for which preclinical toxicology studies have been conducted to assess its safety [2].
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| Molecular Formula |
C22H31CLN2O
|
|---|---|
| Molecular Weight |
392.96262
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| Exact Mass |
338.236
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| Elemental Analysis |
C, 78.06; H, 8.93; N, 8.28; O, 4.73
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| CAS # |
68252-19-7
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| Related CAS # |
Pirmenol hydrochloride; 61477-94-9
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| PubChem CID |
65502
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| Appearance |
Solid powder
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| Density |
1.046g/cm3
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| Boiling Point |
499.6ºC at 760 mmHg
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| Flash Point |
256ºC
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| Index of Refraction |
1.547
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| LogP |
4.298
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
25
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| Complexity |
386
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O.Cl.C[C@@H]1CCC[C@H](C)N1CCCC(C1=CC=CC=N1)(O)C1C=CC=CC=1
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| InChi Key |
APUDBKTWDCXQJA-QIDMFYOTSA-N
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| InChi Code |
InChI=1S/C22H30N2O/c1-18-10-8-11-19(2)24(18)17-9-15-22(25,20-12-4-3-5-13-20)21-14-6-7-16-23-21/h3-7,12-14,16,18-19,25H,8-11,15,17H2,1-2H3/t18-,19+,22?
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| Chemical Name |
4-[(2R,6S)-2,6-dimethylpiperidin-1-yl]-1-phenyl-1-pyridin-2-ylbutan-1-ol
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| Synonyms |
Cl 845; Cl845; Cl-845; Pirmenol; Pirmavar
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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) |
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 | 2.5448 mL | 12.7239 mL | 25.4479 mL | |
| 5 mM | 0.5090 mL | 2.5448 mL | 5.0896 mL | |
| 10 mM | 0.2545 mL | 1.2724 mL | 2.5448 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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