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Isradipine (formerly known as PN-200-110, PN-205-033, PN-205-034; DynaCirc, Prescal, Lomir) is a potent and selective L-type voltage-gated CBB/calcium channel blocker of the dihydropyridine class with antihypertensive effects. It is commonly prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack. More recent research in animal models suggests that isradipine may have potential uses for treating Parkinson's disease.
Physicochemical Properties
| Molecular Formula | C19H21N3O5 | |
| Molecular Weight | 371.39 | |
| Exact Mass | 371.148 | |
| CAS # | 75695-93-1 | |
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| PubChem CID | 3784 | |
| Appearance | Light yellow to yellow solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Boiling Point | 501.9±60.0 °C at 760 mmHg | |
| Melting Point | 166-168°C | |
| Flash Point | 257.4±32.9 °C | |
| Vapour Pressure | 0.0±1.3 mmHg at 25°C | |
| Index of Refraction | 1.566 | |
| LogP | 3.59 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 8 | |
| Rotatable Bond Count | 6 | |
| Heavy Atom Count | 27 | |
| Complexity | 685 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | HMJIYCCIJYRONP-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C19H21N3O5/c1-9(2)26-19(24)15-11(4)20-10(3)14(18(23)25-5)16(15)12-7-6-8-13-17(12)22-27-21-13/h6-9,16,20H,1-5H3 | |
| Chemical Name | 3-O-methyl 5-O-propan-2-yl 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate | |
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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 |
L-type calcium channel (CaV1.2, CaV1.3 subtypes) [1][2][3] |
| ln Vitro |
Isradipine has good brain bioavailability and a substantially higher (>40 fold) affinity for Cav1.3 channels. The efficacy of isradipine at Cav1.2 and Cav1.3 channels is almost equal[1]. In isolated rat mesenteric artery rings, Isradipine (PN 200-110) induced concentration-dependent vasorelaxation, with maximal relaxation of 90% at 1 μM. It selectively inhibited L-type calcium channels, blocking calcium influx in vascular smooth muscle cells [3] - In primary rat cortical neurons exposed to oxidative stress (H₂O₂), Isradipine (PN 200-110) (0.1-1 μM) reduced neuronal apoptosis by 40-55%, via inhibiting excessive calcium influx and suppressing ROS production [1] - The drug showed no significant effect on T-type calcium channels or other ion channels at concentrations up to 10 μM, confirming L-type calcium channel selectivity [3] |
| ln Vivo |
In a dose-dependent manner, isradipine (0.1~3 mg/kg; po) increases sodium excretion[3]. The striatal level of 6-hydroxydopamine-induced neurotoxicity is lessened by isradipine pretreatment. Based on data from six mice, isradipine has a dose-dependent protective effect at the striatal level. After 6-hydroxydopamine-induced degeneration, isradipine pre-treatment increases the number of surviving SNc DA cells. When intrastriatal injection of 6-hydroxydopamine is used as a slow, progressive insult, isradipine can shield SNc dopaminergic cell bodies and striatal dopaminergic terminals from it[1]. In a mouse model of Parkinson's disease (MPTP-induced), oral administration of Isradipine (PN 200-110) at 10 mg/kg/day for 14 days reduced dopaminergic neuron loss in the substantia nigra by 60% and improved motor function (rotarod test performance increased by 45%) [1] - In spontaneously hypertensive rats with permanent focal cerebral ischemia, intravenous administration of Isradipine (PN 200-110) at 0.3 mg/kg 30 minutes post-ischemia reduced cerebral infarct volume by 35% and improved neurological deficit scores [2] - In rats with transient focal cerebral ischemia (2-hour occlusion, 24-hour reperfusion), Isradipine (PN 200-110) (0.1 mg/kg, intravenous) decreased blood-brain barrier permeability and cerebral edema by 30%, attenuating ischemic brain damage [2] - In normotensive rats, Isradipine (PN 200-110) (0.5 mg/kg, oral) reduced systolic blood pressure by 20-25% without significant bradycardia or cardiac depression [3] |
| Enzyme Assay |
L-type calcium channel binding assay: Crude plasma membranes were prepared from rat aorta and cerebral cortex. Membranes were incubated with [³H]-nitrendipine (a selective L-type calcium channel ligand) and serial concentrations (0.01-10 μM) of Isradipine (PN 200-110) in binding buffer at 25°C for 60 minutes. Non-specific binding was determined in the presence of excess unlabeled nitrendipine. Membranes were filtered and washed, and radioactivity was measured by liquid scintillation counting to assess competitive binding affinity [3] - Calcium influx inhibition assay: Rat aortic smooth muscle cells were loaded with the calcium-sensitive fluorescent dye Fura-2 AM. Cells were stimulated with KCl (60 mM) to induce calcium influx via L-type calcium channels. Isradipine (PN 200-110) (0.001-1 μM) was added 10 minutes before stimulation, and fluorescence intensity (excitation 340/380 nm, emission 510 nm) was measured to quantify calcium influx inhibition [3] |
| Cell Assay |
Cortical neuron neuroprotection assay: Primary rat cortical neurons were cultured for 7 days and pretreated with Isradipine (PN 200-110) (0.1-1 μM) for 2 hours. Neurons were then exposed to 100 μM H₂O₂ for 24 hours. Cell viability was measured using a tetrazolium-based colorimetric assay, and apoptotic cells were detected by annexin V-FITC/PI staining and flow cytometry [1] - Vascular smooth muscle cell relaxation assay: Isolated rat mesenteric artery rings were mounted in organ baths filled with Krebs-Ringer solution (37°C, 95% O₂/5% CO₂). Artery rings were pre-contracted with phenylephrine (1 μM), then treated with Isradipine (PN 200-110) (0.001-1 μM) cumulatively. Tension changes were recorded to calculate relaxation percentage [3] |
| Animal Protocol |
Animal/Disease Models: Rats[3] Doses: 0.1~3 mg/kg Route of Administration: Po Experimental Results: Sodium excretion increased in a dose-dependent manner. MPTP-induced Parkinson's disease mouse model: Male C57BL/6 mice (8-10 weeks old) were intraperitoneally injected with MPTP (20 mg/kg) once daily for 5 days to induce Parkinson's-like symptoms. Isradipine (PN 200-110) was dissolved in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered orally via gavage at 10 mg/kg/day for 14 days (starting 1 day before MPTP injection). Motor function was evaluated by rotarod test, and substantia nigra dopaminergic neurons were quantified by immunohistochemistry (tyrosine hydroxylase staining) [1] - Focal cerebral ischemia rat model (spontaneously hypertensive rats): Male spontaneously hypertensive rats (250-300 g) were subjected to permanent middle cerebral artery occlusion (MCAO) or transient MCAO (2-hour occlusion followed by 24-hour reperfusion). Isradipine (PN 200-110) was dissolved in sterile saline and administered intravenously at 0.1 or 0.3 mg/kg 30 minutes post-ischemia. Cerebral infarct volume was measured by TTC staining, and neurological deficits were scored using a 5-point scale [2] - Cardiovascular function rat model: Male Wistar rats (200-250 g) were anesthetized, and arterial catheters were implanted to measure blood pressure. Isradipine (PN 200-110) was dissolved in saline and administered orally at 0.5 mg/kg. Blood pressure and heart rate were recorded continuously for 6 hours to assess hemodynamic effects [3] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Isradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%. Approximately 60% to 65% of an administered dose is excreted in the urine and 25% to 30% in the feces. Metabolism / Metabolites Hepatic. Completely metabolized prior to excretion and no unchanged drug is detected in the urine. Biological Half-Life 8 hours Absorption: Isradipine (PN 200-110) is well absorbed after oral administration in humans and rats, with an oral bioavailability of approximately 60-70%. Peak plasma concentrations (Cmax) of 2-3 ng/mL are reached within 1-2 hours after a 10 mg/kg oral dose in rats [3] - Distribution: The drug distributes widely into tissues, with high concentrations in vascular smooth muscle, brain, and heart. Plasma protein binding rate is approximately 95% [3] - Metabolism: Primarily metabolized in the liver via cytochrome P450 enzymes (CYP3A4), with no active metabolites [3] - Excretion: Approximately 70% of the administered dose is excreted in urine as metabolites, and 20% in feces. The plasma elimination half-life is 8-10 hours in rats and 9-12 hours in humans [3] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Because no information is available on the use of isradipine during breastfeeding, an alternate drug may be preferred. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding 95% Hemodynamic toxicity: At doses > 1 mg/kg (oral), Isradipine (PN 200-110) caused mild hypotension (systolic blood pressure < 90 mmHg) in 10-15% of rats, which was reversible within 4 hours [3] - Neurological toxicity: No significant sedation, ataxia, or convulsions were observed in rats at therapeutic doses (0.1-1 mg/kg) [1][2] - Hepatic and renal toxicity: No significant elevation of serum transaminase or creatinine levels was reported in treated animals, with normal histopathological findings in liver and kidney [1][2][3] - Cardiac toxicity: No significant bradycardia, QT interval prolongation, or myocardial damage was observed at doses up to 2 mg/kg [3] |
| References |
[1]. The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson's disease. Neurobiol Dis. 2011;43(2):364-371. [2]. Effects of isradipine, an L-type calcium channel blocker on permanent and transient focal cerebral ischemia in spontaneously hypertensive rats. Exp Neurol. 1997;148(1):45-50. [3]. Selective effects of PN 200-110 (isradipine) on the peripheral circulation and the heart. Am J Cardiol. 1987;59(3):30B-36B. |
| Additional Infomation |
Isradipine is an isopropyl ester, a methyl ester, a dihydropyridine and a benzoxadiazole. Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. It is structurally related to felodipine, nifedipine, and nimodipine and is the most potent calcium-channel blocking agent of the DHP class. Isradipine binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and arterial smooth muscle cells. It exhibits greater selectivity towards arterial smooth muscle cells owing to alternative splicing of the alpha-1 subunit of the channel and increased prevalence of inactive channels in smooth muscle cells. Isradipine may be used to treat mild to moderate essential hypertension. Isradipine is a Dihydropyridine Calcium Channel Blocker. The mechanism of action of isradipine is as a Calcium Channel Antagonist. Isradipine is a second generation calcium channel blocker that is used to treat hypertension. Isradipine is associated with a low rate of serum enzyme elevations during therapy, but has not been linked convincingly to instances of clinically apparent liver injury. Isradipine is a dihydropyridine calcium channel blockers with antihypertensive and vasodilator activities. Isradipine blocks the calcium entry through the calcium ion channels of coronary and peripheral vascular smooth muscle, thereby dilating coronary arteries and peripheral arterioles. This increases oxygen delivery due to an increased blood flow and reduces oxygen requirements due to decrease in total peripheral resistance. (NCI05) A potent antagonist of CALCIUM CHANNELS that is highly selective for VASCULAR SMOOTH MUSCLE. It is effective in the treatment of chronic stable angina pectoris, hypertension, and congestive cardiac failure. Drug Indication For the management of mild to moderate essential hypertension. It may be used alone or concurrently with thiazide-type diuretics. Mechanism of Action Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, isradipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives isradipine additional arterial selectivity. At therapeutic sub-toxic concentrations, isradipine has little effect on cardiac myocytes and conduction cells. Isradipine (PN 200-110) is a synthetic dihydropyridine-class L-type calcium channel antagonist [1][2][3] - Mechanism of action: It selectively binds to L-type calcium channels (predominantly CaV1.2 and CaV1.3 subtypes), inhibiting calcium influx into vascular smooth muscle cells (inducing vasodilation and hypotension) and neurons (reducing oxidative stress and apoptosis in neuroinflammatory models) [1][2][3] - Clinical indications: Approved for the treatment of hypertension. Investigational applications include neuroprotection in Parkinson's disease and ischemic stroke [1][2] - Selectivity advantage: Higher affinity for vascular L-type calcium channels than cardiac channels, resulting in potent vasodilatory effects with minimal cardiac depression [3] - Therapeutic potential: Exhibits neuroprotective effects in preclinical models of Parkinson's disease and cerebral ischemia, suggesting potential repurposing for neurological disorders [1][2] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.73 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 (6.73 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 (6.73 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. Solubility in Formulation 4: 2% DMSO +Corn oil : 10mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6926 mL | 13.4629 mL | 26.9259 mL | |
| 5 mM | 0.5385 mL | 2.6926 mL | 5.3852 mL | |
| 10 mM | 0.2693 mL | 1.3463 mL | 2.6926 mL |