N-type Ca2+ channel (rat dorsal root ganglion neurons), [1]
- Vascular L-type calcium channels [2]
- Phosphatidylinositol 3-kinase (PI3K) pathway (involved in neuroprotective effect), [3]

In neurons pretreated with omegaCgTx plus omegaAgTx, celidipine inhibits the L-type current with an IC50 of 100 nM[1]. Cilnidipine's IC50 with regard to the N-type current is 200 nM[1]. With an IC50 of 10 nM at 10 min, clinidipine dose- and time-dependently inhibits the contractions of rat aortic rings caused by depolarization and Ca2+[2]. When exposed to more than 200 μM of Cilnidipine, the viability of nPC12 cells decreases slightly, but does not change significantly up to 150 μM of the drug[3]. After two hours of treatment at 100 μM, cilnidipine increases the expression of p85aPI3K, p-Akt, p-GSK-3β, and heat shock transcription factor (HSTF-1), while cytosolic cytochrome c, activated caspase 3, and cleaved PARP levels decrease[3].

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In rat dorsal root ganglion neurons, Cilnidipine inhibited N-type Ca2+ channel currents in a concentration-dependent manner, with significant suppression observed at relevant concentrations without complete blockage [1]
- In vascular smooth muscle-related in vitro models, Cilnidipine acted as a slow-acting blocker of L-type calcium channels, exerting inhibitory effects on channel activity independent of protein kinase C (PKC) targeting [2]
- In neuronal cells subjected to oxidative stress, Cilnidipine scavenged free radicals, reduced oxidative damage, and activated the PI3K pathway, thereby enhancing neuronal survival and exerting neuroprotective effects [3]

In rat dorsal root ganglion neurons, cilnidipine has strong inhibitory effects on both L-type and N-type voltage-dependent Ca2+ channels[1]. The use of 10 mg/kg of cilnidipine and 10 mg/kg of nicodipine greatly reduces the behavioral abnormalities brought on by immobilization stress, restores deficit memories, and normalizes corticosterone levels[4]. Both nicodipine and clonidipine have similar positive effects on immobilized mice under stress[4]. In 2K1C renal hypertensive dogs, oral Cilnidipine (3 mg/kg) significantly reduces both systolic and diastolic blood pressure one hour after administration[5].

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In 2K1C renal hypertensive dogs, repeated oral administration of Cilnidipine produced significant antihypertensive effects, effectively reducing elevated blood pressure [5]
- In immobilization-stressed mice, Cilnidipine exhibited anti-stress effects, as evidenced by modulation of stress-related physiological parameters and behaviors compared to control groups [4]

For N-type Ca2+ channel activity assay: Isolated rat dorsal root ganglion neurons were used, and Ca2+ channel currents were recorded using patch-clamp technique. Cilnidipine was applied at different concentrations, and current changes were measured to evaluate inhibitory effects [1]
- For L-type calcium channel activity assay: Vascular tissue-derived preparations were used to assess channel function. Cilnidipine was incubated with the preparations, and changes in L-type Ca2+ channel activity were detected to determine blocking efficiency, with PKC activity also measured to confirm non-targeting effect [2]

Cell Viability Assay
Cell Types: Neuronally differentiated PC12 (nPC12) cells
Tested Concentrations: 0, 1, 5, 10, 25, 50, 100, 150, and 200 μM
Incubation Duration: Treated for 2 hrs (hours); cell viability was measured after 24 hrs (hours)
Experimental Results: Cell viability was not affected by low concentrations up to 150 μM, but it was slightly diminished at 200 μM.

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Western Blot Analysis
Cell Types: nPC12 cells
Tested Concentrations: 100 μM
Incubation Duration: 2 hrs (hours)
Experimental Results: Increased the IRs of p58a PI3K, p-Akt, p-GSK-3β, and HSTF-1 and diminished the Immunoreactivities (IRs) of cytosolic cytochrome c, activated caspase 3 (17 kDa), and cleaved PARP (85 kDa).

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For neuronal cell oxidative stress assay: Neuronal cells were exposed to oxidative stressors, and Cilnidipine was added at specific concentrations. Free radical levels were detected, and PI3K pathway-related protein expression was analyzed to evaluate neuroprotective mechanisms [3]
- For dorsal root ganglion neuron assay: Rat dorsal root ganglion neurons were cultured and patched using whole-cell patch-clamp method. Cilnidipine was administered via bath application, and N-type Ca2+ channel current amplitudes were recorded and analyzed [1]

Animal/Disease Models: Swiss albino mice weighing 25±5 g[4]
Doses: 5 and 10 mg/kg
Route of Administration: administered ip 30 min prior to immobilization stress
Experimental Results: Cilnidipine (10 mg/kg, ip) and nimodipine (10 mg/kg, ip) 30 min prior to subjecting immobilization stress resulted in significant attenuation of immobilization stress-induced decrease in locomotor activity. Administration with Cilnidipine (5 mg /kg, ip) and Nimodipine (5 mg/kg, ip) did not show any significant effect on the stressed mice. Administration of Cilnidipine (10 mg/kg, ip) and Nimodipine (10 mg/kg, ip) in the non -stressed mice, and vehicle in the stressed mice did not modulate locomotor activity in a significant manner.

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For 2K1C renal hypertensive dogs: Dogs were induced to develop renal hypertension via the 2K1C method. Cilnidipine was prepared as an oral formulation, administered repeatedly at specified doses, and blood pressure was measured at regular intervals to assess antihypertensive efficacy [5]
- For immobilization-stressed mice: Mice were subjected to immobilization stress. Cilnidipine was administered via an appropriate route (not specified in public data) at specific doses, and stress-related indicators (physiological and behavioral) were evaluated after treatment [4]

Absorption, Distribution and Excretion
Cinidipine is rapidly absorbed, reaching peak plasma concentration within 2 hours. Its distribution is primarily concentrated in the liver, kidneys, plasma, and other tissues. After repeated oral administration, cilnidipine accumulation in tissues is not significant. Cinidipine has been reported to have extremely low bioavailability, approximately 13%. This low bioavailability is attributed to its low water solubility and high permeability. Therefore, efforts have been made to find innovative formulations that can significantly improve the bioavailability of this drug. One such formulation corresponds to the formation of polymer nanoparticles, which can increase bioavailability by 2.5-3 times. Cinidipine is primarily excreted in the urine, accounting for approximately 20% of the administered dose, with the remaining 80% excreted in the feces. Dihydropyridine drugs (such as cilnidipine) typically have a large volume of distribution. Metabolism/Metabolites Cinidipine is primarily metabolized by the liver and kidneys. It is rapidly metabolized in liver microsomes via a dehydrogenation process. The main isoenzyme involved in the dehydrogenation of the dihydropyridine ring of cilnidipine is CYP3A.

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Biological Half-Life
The hypotensive half-life of cilnidipine is approximately 20.4 minutes.

Protein Binding
Cinidipine has a very high protein binding rate, reaching up to 98% of the administered dose.

[1]. Effect of cilnidipine, a novel dihydropyridine Ca2+-channel antagonist, on N-type Ca2+ channel in rat dorsal root ganglion neurons. J Pharmacol Exp Ther. 1997 Mar;280(3):1184-91.

[2]. Cilnidipine is a novel slow-acting blocker of vascular L-type calcium channels that does not target protein kinase C. J Hypertens. 2002 May;20(5):885-93.

[3]. Cilnidipine mediates a neuroprotective effect by scavenging free radicals and activating the phosphatidylinositol 3-kinase pathway. J Neurochem. 2009 Oct;111(1):90-100.

[4]. Anti-stress effects of cilnidipine and nimodipine in immobilization subjected mice. Physiol Behav. 2012 Mar 20;105(5):1148-55.

[5]. [Antihypertensive effects of repeated oral administration of cilnidipine, a novel calcium antagonist, in 2K1C renal hypertensive dogs]. Nihon Yakurigaku Zasshi. 1995 Oct;106(4):279-87.

Cinidipine is a diesterized 1,4-dihydropyridine-3,5-dicarboxylic acid. It is a calcium channel blocker used as an antihypertensive drug. It has a dual role as a calcium channel blocker, antihypertensive drug, and cardiovascular drug. It is a dihydropyridine compound containing 2-methoxyethyl ester and a C-nitro compound. Cinidipine is a dihydropyridine calcium antagonist. It was jointly developed by Fuji Neikokusho Pharmaceutical Co., Ltd. and Ajinomoto Co., Ltd. of Japan and approved for marketing in 1995. Compared with other calcium antagonists, cinidipine, in addition to acting on L-type calcium channels like most calcium antagonists, can also act on N-type calcium channels present in sympathetic nerve endings. This drug has been approved for marketing in China, Japan, South Korea, India, and several European Union countries. Indications Cinidipine is indicated for the treatment of hypertension to protect end organs. It has been reported to be effective in elderly patients and patients with diabetes and proteinuria. Cisnidipine is increasingly used to treat patients with chronic kidney disease. Hypertension refers to elevated blood pressure. Blood pressure is generated by the pressure of blood pumped by the heart against the walls of blood vessels. Therefore, hypertension occurs when the pressure in blood vessels is too high, and this pressure can damage blood vessels. Mechanism of Action Cisnidipine lowers blood pressure by blocking calcium ions from entering the bloodstream and inhibiting vasoconstriction, thereby acting on L-type calcium channels in blood vessels. Cisnidipine also acts on N-type calcium channels located at the sympathetic nerve endings, inhibiting the release of norepinephrine, thus inhibiting stress-induced hypertension. Pharmacodynamics In vitro and in vivo studies have shown that cisnidipine has an anti-sympathetic effect. It lowers blood pressure safely and effectively without causing excessive drops in blood pressure or tachycardia.

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Cinnidipine is a novel dihydropyridine calcium channel antagonist with dual effects on both N-type and L-type calcium channels[1][2]
- Cinnidipine's neuroprotective effect is closely related to its scavenging of free radicals and activation of the PI3K pathway, providing a potential target for the treatment of neuronal damage[3]
- Compared with nimodipine, Cinnidipine showed similar anti-stress effects in fixed mice, indicating its potential application value in the treatment of stress-related diseases[4]

C27H28N2O7

492.52

492.189

132203-70-4

Cilnidipine-d7

5282138

Light yellow to green yellow solid powder

1.2±0.1 g/cm3

652.6±55.0 °C at 760 mmHg

97-99°C

348.5±31.5 °C

0.0±2.0 mmHg at 25°C

1.592

5.36

1

8

11

36

896

0

CC1=C(C(C(=C(N1)C)C(=O)OC/C=C/C2=CC=CC=C2)C3=CC(=CC=C3)[N+](=O)[O-])C(=O)OCCOC

KJEBULYHNRNJTE-DHZHZOJOSA-N

InChI=1S/C27H28N2O7/c1-18-23(26(30)35-14-8-11-20-9-5-4-6-10-20)25(21-12-7-13-22(17-21)29(32)33)24(19(2)28-18)27(31)36-16-15-34-3/h4-13,17,25,28H,14-16H2,1-3H3/b11-8+

3-O-(2-methoxyethyl) 5-O-[(E)-3-phenylprop-2-enyl] 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.08 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.08 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.

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Solubility in Formulation 3: 5% DMSO +Corn oil : 7 mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)