Calcium sensitizer; increases myofilament sensitivity to Ca²⁺; may interact with troponin-tropomyosin complex [2]

Phosphodiesterase III (PDE III) inhibitor (activity weaker than milrinone) [3]

Modulates vascular reactivity via Rho-kinase, protein kinase C (PKC), and protein kinase G (PKG) pathways [3]

Senazodan (HCl) raises myosin ATPase activity and seems to have a direct impact on the dynamics of the actin-myosin cross-bridge [1]. The tonicity increases in response to concentration after using senazodan hydrochloride. Purified cardiac troponin C and myofilaments exhibit enhanced Ca2+ binding when exposed to senazodan (HCl). By decreasing PDE III, senazodan (hydrochloride) also improves the contractility of the papillary muscles in guinea pigs [2]. Senazodan (0.1 nM~0.1 mM) hydrochloride shown a substantial reduction in the superior mesenteric artery's (SMA) contractile response to norepinephrine (NE) following hemorrhagic shock as compared to the normal control group. The pretreatment with senazodan (0.01 mM) hydrochloride inhibited the effects of Ang II and caused a shift in the concentration-response curve of Ca2+ to the right as compared to the Ang II alone group [3].

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In superior mesenteric artery (SMA) rings from hemorrhagic shock rats, MCI-154 (10⁻⁷, 10⁻⁶, 10⁻⁵, 10⁻⁴ mol/L) further decreased contractile responses to norepinephrine (NE) in a concentration-dependent manner. The maximal contraction (Emax) to NE was significantly reduced compared to shock control group (e.g., shock control Emax = 1.273±0.084 g/mg tissue; MCI-154 10⁻⁵ mol/L Emax = 0.744±0.100 g/mg tissue; MCI-154 10⁻⁴ mol/L Emax = 0.231±0.077 g/mg tissue). The pD₂ value was significantly lower only at the highest concentration (6.003±0.202) compared to shock control (6.474±0.208). [3]

MCI-154 (10⁻⁷ to 10⁻⁴ mol/L) further decreased contractile responses to extracellular Ca²⁺ ([Ca²⁺]₀) in SMA from hemorrhagic shock rats. The maximal responses to [Ca²⁺]₀ in MCI-154 groups were decreased to 79.8%, 65.5%, 54.6%, and 37.2% of shock control group response, respectively. [3]

MCI-154 (10⁻⁵ mol/L) partially inhibited Angiotensin II (Ang II, 10⁻⁹ mol/L)-induced increase in contractile responses to [Ca²⁺]₀ of SMA from hemorrhagic shock rats. The concentration-response curve of Ca²⁺ was shifted to the right compared to Ang II-alone group (P<0.01). [3]

MCI-154 (10⁻⁵ mol/L) significantly antagonized PMA (10⁻⁷ mol/L, a PKC agonist)-induced increase in contractile responses to [Ca²⁺]₀ of SMA. The concentration-response curve of Ca²⁺ was shifted to the right compared to PMA-alone group (P<0.01). [3]

KT-5823 (10⁻⁶ mol/L, a PKG antagonist) blocked MCI-154-induced decrease of contractile responses to [Ca²⁺]₀ of SMA, shifting the concentration-response curve of Ca²⁺ to the left compared to MCI-154-alone group (P<0.01). [3]

In skinned cardiac fibers, senazodan produces a concentration-dependent increase in tension development. It enhances Ca²⁺ binding to myofilaments and to purified cardiac troponin C. [2]

Senazodan enhances contractility in guinea-pig papillary muscles by inhibiting PDE III. [2]

The pressor action of norepinephrine (NE) is lessened by senazodan (0.1~2.0 mg/kg; infusion through left femoral vein cannula) (hydrochloride) [3]. Senazodan (0.1 mg/kg; intravenous injection; hydrochloride) considerably reduced left ventricular end-diastolic pressure (LVEDP) and dramatically increased LVSP, IP, MC, and Lo without significantly changing heart rate [4].

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In hemorrhagic shock rats (MAP maintained at 30 mmHg for 2 hours), MCI-154 (0.1, 0.5, 1.0, 2.0 mg/kg continuous intravenous infusion over 30 minutes with Ringer’s solution) further decreased the pressor effect of norepinephrine (NE, 3 μg/kg bolus IV) compared to shock control group. The NE-induced pressor response was significantly reduced at all MCI-154 doses, but no significant dose-dependent differences were observed among the four doses. [3]

Animal/Disease Models: Wistar rat (200~250 g) [3]
Doses: 0.1~2.0 mg/kg
Route of Administration: Left femoral vein intubation infusion
Experimental Results: Reduce the pressor effect of norepinephrine (NE).

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Animal/Disease Models: Rabbit [4]
Doses: 0.1 mg/kg
Route of Administration: intravenous (iv) (iv)injection
Experimental Results: LVSP, IP, MC, and Lo were all Dramatically increased, heart rate had no significant change, and left ventricular end-diastolic pressure (LVEDP) was Dramatically increased. reduce.

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In vivo hemorrhagic shock model: Male Wistar rats (200-250 g) were anesthetized with sodium pentobarbital (30 mg/kg intraperitoneal). Both femoral arteries and one femoral vein were catheterized. Mean arterial pressure (MAP) was decreased from 107.1±8.6 mmHg to 30 mmHg by bleeding within 10 minutes and maintained at this level for 2 hours by removing or reinfusing blood. After the shock period, MCI-154 (0.1, 0.5, 1.0, 2.0 mg/kg) was infused continuously for 30 minutes with 3 volumes of Ringer’s solution (total infusion volume 2.18±0.37 mL/kg/min IV). The pressor effect of NE (3 μg/kg bolus IV) was measured at baseline (pre-hemorrhage), at end of hemorrhage (0 h), and at 0.5, 1, 2, and 4 hours after drug administration. The sham-operated group underwent surgery without hemorrhage or fluid infusion. The shock control group received equal volume Ringer’s solution. [3]

In vitro vascular reactivity assay: Superior mesenteric arteries (SMAs) were obtained from normal or hemorrhagic shock rats. SMA rings (2-3 mm long) were mounted in organ chambers containing Krebs-Henseleit (K-H) solution (118 mmol/L NaCl, 4.7 mmol/L KCl, 25 mmol/L NaHCO₃, 1.03 mmol/L KH₂PO₄, 0.45 mmol/L MgSO₄·7H₂O, 2.5 mmol/L CaCl₂, 11.1 mmol/L glucose, pH 7.4), continuously bubbled with 95% O₂/5% CO₂, temperature maintained at 25°C, preload 0.5 g. After 1.5-hour equilibration, SMA rings in MCI-154 groups were incubated with MCI-154 (10⁻⁷, 10⁻⁶, 10⁻⁵, 10⁻⁴ mol/L) for 30 minutes, then contractile responses to NE (10⁻⁹ to 10⁻⁴ mol/L) were determined. [3]

In vitro Ca²⁺ contractile response assay: SMA rings were equilibrated in K-H solution for 2 hours, then switched to nominally calcium-free depolarizing high-K solution (2.7 mmol/L NaCl, 120 mmol/L KCl, 25 mmol/L NaHCO₃, 1.03 mmol/L KH₂PO₄, 0.45 mmol/L MgSO₄·7H₂O, 11.1 mmol/L glucose, pH 7.4). After 10-20 minutes equilibration, SMA rings in MCI-154 groups were incubated with MCI-154 (10⁻⁷ to 10⁻⁴ mol/L) for 30 minutes, then CaCl₂ was added cumulatively (3×10⁻⁵, 1×10⁻⁴, 3×10⁻⁴, 1×10⁻³, 2×10⁻³, 6×10⁻³, 1×10⁻², 3×10⁻² mol/L) to obtain concentration-response curves. [3]

Mechanism study with modulators: SMA rings from hemorrhagic shock rats were incubated with Ang II (10⁻⁹ mol/L, 10 min), PMA (10⁻⁷ mol/L, 10 min), or KT-5823 (10⁻⁶ mol/L, 10 min), alone or after MCI-154 pretreatment (10⁻⁵ mol/L for 30 min), then contractile responses to Ca²⁺ were measured as above. [3]

[1]. Pharmacokinetics and pharmacodynamics of intravenous inotropic agents. Clin Pharmacokinet. 2004;43(3):187-203.

[2]. Erhardt L. An emerging role for calcium sensitisation in the treatment of heart failure. Expert Opin Investig Drugs. 2005 Jun;14(6):659-70.

[3]. Effects of MCI-154 on vascular reactivity and its mechanisms after hemorrhagic shock in rats. J Cardiovasc Pharmacol. 2006;47(6):751-757.

[4]. Effects of MCI-154, a calcium sensitizer, on cardiac dysfunction in endotoxic shock in rabbits. Shock. 2000;13(6):459-463.

See also: Senazodan (Note moved to).

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Senazodan (MCI-154) is an investigational calcium sensitizer that has been studied for its positive inotropic effects. It enhances cardiac contractility by increasing Ca²⁺ sensitivity of the contractile apparatus. At higher concentrations (≥10⁻⁵ mol/L), it can inhibit cAMP-dependent phosphodiesterase (PDE) III, but this inhibitory action is weaker than that of milrinone and some other Ca²⁺ sensitizers. It is considered a relatively pure Ca²⁺ sensitizer with minor PDE III inhibitory activity. [3]

In hemorrhagic shock, MCI-154 worsens vascular hyporeactivity and decreases contractile responses to extracellular Ca²⁺, which may be regulated by Rho-kinase, PKC, and PKG pathways. This suggests that if used clinically, dosage and fluid resuscitation must be carefully considered, and concomitant use of vasoconstrictors (e.g., vasopressin) might be necessary. [3]

C15H15CLN4O

302.76

302.093

98326-33-1

Senazodan;98326-32-0

123941

Light yellow to yellow solid powder

492.4ºC at 760 mmHg

251.6ºC

2.374

3

4

3

21

368

0

NYQCKFLLTCINSJ-UHFFFAOYSA-N

InChI=1S/C15H14N4O.ClH/c20-15-6-5-14(18-19-15)11-1-3-12(4-2-11)17-13-7-9-16-10-8-13;/h1-4,7-10H,5-6H2,(H,16,17)(H,19,20);1H

3-[4-(pyridin-4-ylamino)phenyl]-4,5-dihydro-1H-pyridazin-6-one;hydrochloride

Senazodan hydrochloride MCI154 MCI 154MCI-154

2934.99.9001

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 (e.g. under nitrogen), avoid exposure to moisture and light.

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

DMSO : ~67.5 mg/mL (~222.95 mM)
H2O : ~25 mg/mL (~82.57 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.26 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 (8.26 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.

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