Efonidipine targets voltage-gated calcium channels (Cavs), specifically inhibiting both L-type and T-type channels. It inhibits Cav1.2a (hamster L-type) with an IC50 of 1.8 nM and Cav3.2 (human T-type) with an IC50 of 350 nM. This dual inhibition reduces calcium influx in vascular smooth muscle and cardiac cells, leading to vasodilation, decreased cardiac automaticity, and antihypertensive effects. The compound shows higher potency for L-type over T-type channels.

In vitro, Efonidipine inhibits L-type Cav1.2a with an IC50 of 1.8 nM and T-type Cav3.2 with an IC50 of 350 nM. In H295R adrenal cells, it modulates steroidogenesis by increasing StAR mRNA expression and DHEA-S production while suppressing aldosterone and cortisol biosynthesis, at least in part through suppression of 11-β-hydroxylase. These activities demonstrate its dual channel-blocking and endocrine-modulating properties in cell-based systems.

In vivo, Efonidipine exhibits antihypertensive effects through vasodilation, increasing coronary blood flow. Its negative chronotropic effect reduces heart rate by acting on the sinoatrial node. The compound's dual L/T-type calcium channel blockade contributes to its cardiovascular profile, with T-type inhibition particularly relevant for reducing heart rate without significant negative inotropic effects. Animal model studies support its efficacy in lowering blood pressure and improving cardiac function.

In vitro enzyme/receptor binding assays typically measure displacement of radiolabeled calcium channel ligands (e.g., [³H]nitrendipine for L-type, [¹²⁵I]Ta-conotoxin for T-type) using membrane preparations from cells expressing recombinant Cav1.2 or Cav3.2 channels. Competition binding experiments are performed with varying concentrations of Efonidipine to calculate IC50 values. Alternatively, calcium flux assays using fluorescent dyes (e.g., Fluo-4) in cells expressing specific channel subtypes can assess functional inhibition of channel activity.

For in vitro cellular assays, H295R human adrenal cortical carcinoma cells are cultured and treated with Efonidipine at various concentrations. Following treatment, steroidogenic acute regulatory protein (StAR) mRNA expression is measured by qRT-PCR, and hormone levels (DHEA-S, aldosterone, cortisol) in culture media are quantified by ELISA or radioimmunoassay. Calcium channel inhibition can be assessed in cardiomyocytes or vascular smooth muscle cells using patch-clamp electrophysiology or calcium imaging with fluorescent indicators to measure depolarization-induced calcium influx.

In vivo animal studies typically utilize spontaneously hypertensive rats (SHR) or other hypertensive models. Efonidipine is administered orally or intravenously, and blood pressure is monitored via telemetry or tail-cuff plethysmography. Heart rate is measured simultaneously to assess chronotropic effects. Coronary blood flow may be evaluated using Doppler flow probes. Efficacy is compared to vehicle controls and reference calcium channel blockers. Dosing regimens vary; typical oral doses range from 1-10 mg/kg.

Absorption, Distribution and Excretion
The metabolism of evodilator was studied in mice. The estimated radioactive absorption rate, based on total bile and urinary excretion, was approximately 62%. The highest radioactivity was observed in the gastrointestinal tract and liver, followed by the adrenal glands, indicating high metabolic rates in these sites. Two hours after ingestion, the unchanged drug accounted for 47.7% of the total radioactivity in plasma, suggesting a low first-pass effect compared to other drugs in the same class. The major metabolites of NZ-105 in plasma were: N-debenzylidene compound (DBZ), N-dephenyl compound (DPH), oxidative deamination compound (AL), the pyridine compound corresponding to AL (ALP), and unknown metabolites M-1 and M-25. The metabolic pathway of NZ-105 includes N-debenzylidene, N-dephenyllidene, oxidative deamination, ester hydrolysis, and epoxidation of 1,4-dihydropyridine to the corresponding pyridine. Evodipine, also known as NZ-105, is primarily excreted via the biliary system.

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Metabolism/Metabolites
Studies have shown that evodidipine is less prone to first-pass metabolism than similar drugs, with its dihydropyridine ring primarily undergoing oxidation after side-chain metabolism. Evodipine is highly lipophilic, enabling it to enter phospholipid-rich cell membranes and reach the dihydropyridine binding sites of calcium channel targets. Evodipine is primarily metabolized in the liver. Its metabolites include N-dephenylevodipine (DPH), deaminoevodipine (AL), and N-debenzylidene evodidipine (DBZ). Both of these metabolites possess calcium antagonist activity. One study showed that DBZ and DPH have approximately two-thirds and one-third of the vasodilatory capacity of the unmetabolized drug, respectively. Studies have shown that after oral administration of evodidipine hydrochloride, most of its pharmacological effects are produced by the parent drug, while its metabolites have minimal impact on its therapeutic efficacy. A study of six healthy volunteers found no significant excretion of the parent drug in their urine. Urine samples collected within 24 hours after oral administration of edofodipine showed that 1.1% of the dose was excreted as desamidoedifodipine and 0.5% as a pyridine analogue of desamidoedifodipine.
Biobiological half-life
Peak plasma concentrations are reached approximately 1.5 to 3.67 hours after administration. The half-life is approximately 4 hours.
Efonidipine is orally bioavailable with favorable pharmacokinetic properties for once-daily dosing. As a calcium channel blocker, it undergoes hepatic metabolism, primarily via CYP3A4, with metabolites excreted in urine and feces. The compound has a relatively long half-life supporting sustained antihypertensive effects. Peak plasma concentrations are achieved within a few hours post-administration. Food intake may affect absorption; hence it is typically administered under standardized conditions in preclinical studies.

Preclinical toxicity studies indicate that Efonidipine is generally well-tolerated at therapeutic doses. Common adverse effects associated with calcium channel blockers include peripheral edema, headache, flushing, and dizziness, which are mechanism-based. High doses may cause excessive vasodilation leading to hypotension and reflex tachycardia. In chronic studies, no significant organ toxicity was reported at clinically relevant exposures. Safety pharmacology studies evaluate effects on cardiovascular, respiratory, and central nervous systems.

[1]. Efonidipine, a Ca(2+)-channel blocker, enhances the production of dehydroepiandrosterone sulfate in NCI-H295R human adrenocortical carcinoma cells. Tohoku J Exp Med. 2011;224(4):263-71.

[2]. Effects of efonidipine, an L- and T-type calcium channel blocker, on the renin-angiotensin-aldosterone system in chronic hemodialysis patients. Int Heart J. 2010 May;51(3):188-92.

[3]. Beneficial effects of the dual L- and T-type Ca2+ channel blocker efonidipine on cardiomyopathic hamsters. Circ J. 2007 Dec;71(12):1970-6.

[4]. Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology. 2006;78(1):11-20.

2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphacyclohexane-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid ester is a carboxylic acid ester formed by the condensation of the carboxyl group of 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphacyclohexane-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid with the hydroxyl group of 2-[benzyl(phenyl)amino]ethanol. It is a C-nitro compound, a carboxylic acid ester, a tertiary amine compound, and a dihydropyridine compound. Ifodipine is a dihydropyridine calcium channel blocker commercially manufactured by Shionogi & Co., Ltd. of Japan. It was initially marketed in 1995 under the brand name Landel. Studies have shown that this drug blocks not only L-type calcium channels but also T-type calcium channels. It is also used to treat atherosclerosis and acute renal failure. This drug is also known as NZ-105 and has undergone multiple pharmacokinetic studies in animals. Drug Indications: For the treatment of hypertension. Mechanism of Action: This drug inhibits both L-type and T-type calcium channels, leading to vasodilation and decreased cardiac automaticity. Efundiprine has a negative chronotropic effect, reducing heart rate. Efundiprine acts on sinoatrial node cells by inhibiting T-type calcium channel activity, prolonging late phase 4 depolarization of the sinoatrial node action potential, thereby reducing heart rate. This is associated with decreased myocardial oxygen consumption and increased coronary blood flow, thus alleviating myocardial ischemia. Efundiprine can increase the glomerular filtration rate (GFR) without increasing glomerular pressure or filtration fraction. This increase helps prevent kidney damage commonly associated with hypertension. Efodipine increases renal sodium excretion by inhibiting aldosterone synthesis and adrenal secretion. It is also claimed to inhibit aldosterone-induced renal parenchymal fibrosis. L-type calcium channel blockers (such as evokine) preferentially dilate the afferent arterioles of the kidney, while L/T and L/N type calcium channel blockers can potently dilate both afferent and efferent arterioles. The different effects of calcium channel blockers on renal microcirculation are reflected in changes in glomerular capillary pressure and subsequent kidney damage: L-type calcium channel blockers promote an increase in glomerular capillary pressure, while L/T and L/N type calcium channel blockers alleviate glomerular hypertension. This supports the theory that L/T type calcium channel blockers may be beneficial for renal hypertension. Efodipine is a long-acting drug due to its low dissociation constant. Recent studies have shown that evokine can reduce plasma aldosterone levels in patients undergoing regular hemodialysis, providing additional cardiovascular protection for patients with end-stage renal disease.

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Pharmacodynamics
Dihydropyridine drugs (DHPs) primarily act on L-type calcium channels, mainly causing reflex tachycardia, thus negatively impacting cardiac function. This leads to a decrease in blood pressure and an increase in heart rate. Efradipine acts on both L-type and T-type calcium channels. Because inhibiting T-type calcium channels in the sinoatrial node (SA node) can reduce reflex tachycardia, this drug has a positive effect on cardiac pacing. The effect of edofradipine on heart rate, especially on reflex tachycardia, deserves special attention due to its unique role compared to other drugs in its class.

Efonidipine (NZ-105) is a research-grade calcium channel blocker. It is distinguished from other dihydropyridines by its dual L/T-type blocking activity, which may confer advantages in treating conditions where T-type channels play a role, such as certain arrhythmias or renal disease. The compound is available for preclinical research purposes only and is not approved for human therapeutic use in most regions. Its mechanism involves both vasodilation and reduced cardiac automaticity.

C34H38N3O7P

631.6552

631.244

111011-63-3

Efonidipine hydrochloride monoethanolate;111011-76-8;Efonidipine hydrochloride;111011-53-1

119171

Off-white to light yellow solid powder

1.3±0.1 g/cm3

746.9±60.0 °C at 760 mmHg

405.5±32.9 °C

0.0±2.5 mmHg at 25°C

1.625

6.99

1

9

10

45

1170

0

P1(C2=C(C([H])([H])[H])N([H])C(C([H])([H])[H])=C(C(=O)OC([H])([H])C([H])([H])N(C3C([H])=C([H])C([H])=C([H])C=3[H])C([H])([H])C3C([H])=C([H])C([H])=C([H])C=3[H])C2([H])C2C([H])=C([H])C([H])=C(C=2[H])[N+](=O)[O-])(=O)OC([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])O1

NSVFSAJIGAJDMR-UHFFFAOYSA-N

InChI=1S/C34H38N3O7P/c1-24-30(33(38)42-19-18-36(28-15-9-6-10-16-28)21-26-12-7-5-8-13-26)31(27-14-11-17-29(20-27)37(39)40)32(25(2)35-24)45(41)43-22-34(3,4)23-44-45/h5-17,20,31,35H,18-19,21-23H2,1-4H3

2-(N-benzylanilino)ethyl 5-(5,5-dimethyl-2-oxo-1,3,2λ5-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate

NZ105; NZ 105; NZ-105

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

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

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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