N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl}benzenesulfonamide

Product NameN-{2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl}benzenesulfonamide
CAS891016-02-7
MFC23H31N3O3S
MW429.58
EINECS816-721-6
MOL File891016-02-7.mol

Chemical Properties

Boiling point	589.3±60.0 °C(Predicted)
Density	1.26±0.1 g/cm3(Predicted)
storage temp.	Store at -20°C
solubility	DMSO : 50 mg/mL (116.39 mM; Need ultrasonic)
pka	11.63±0.40(Predicted)
form	Solid
color	White to off-white
InChIKey	OVTXOMMQHRIKGL-UHFFFAOYSA-N
SMILES	C1(S(NC2CCCCC2N2CCN(C3=CC=CC=C3OC)CC2)(=O)=O)=CC=CC=C1

Safety Information

WGK Germany	WGK 3
Storage Class	11 - Combustible Solids

Usage And Synthesis

Uses

ML-SI3 is a mixture of cis/trans ML-SI3 (HY-139426A), which is a TRPML1/2 channel inhibitor with IC50s of 4.7 μM and 1.7 μM, respectively. ML-SI3 also inhibits lysosomal calcium efflux and blocks downstream TRPML1-mediated autophagy. The cis/trans ML-SI3 (HY-139426A) components of ML-SI3 are TRPML2 activators with EC50s of 3.3 μM and 9.4 μM, respectively[1][2].

Biological Activity

ML-SI3 is a 4-diastereomer racemate (2 cis and 2 trans isomers) with a cation channel TRPML1-blocking (IC50 = 3.1 μM/trans, 18.5 μM/cis against 5 μM ML-SA1-induced cellular calcium response) and TRPML2-activating activity (EC50 = 3.3 μM/trans, 9.4 μM/cis), while exhibiting much weaker TRPML3 potency (EC50 = 28.5 μM/trans, IC50 = 29.0 μM/cis). ML-SI3 is shown to compete against ML-SA1 for binding the same TRPML1 hydrophobic cavity. Comparing with ML-SI1 (GW405833), ML-SI3 is more potent and not agonist-dependent, effectively antagonizing against TRPML1 activation by both MK6-83 and ML-SA1.

in vivo

ML-SI3 (1.5 mg/kg, i.p., four times) attenuates I/R injury in mouse cardiomyocytes^[6].

Animal Model:	Myocardial Ischemia/reperfusion (I/R) injury mice^[5]
Dosage:	1.5 mg/kg
Administration:	Intraperitoneal injection (i.p.), four times before and during the in vivo I/R (ischemia 30 min and reperfusion 1 day)
Result:	Restored the blocked autophagic fux in the cardiomyocytes subjected to I/R.

IC 50

Schistosome; TRPML1: 4.7 μM (IC₅₀); TRPML2: 1.7 μM (IC₅₀); TRPML3: 12.5 μM (IC₅₀)

References

[1] Rühl P, et al. Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors. Sci Rep. 2021 Apr 15;11(1):8313. DOI:10.1038/s41598-021-87817-4
[2] Leser C, et al. Chemical and pharmacological characterization of the TRPML calcium channel blockers ML-SI1 and ML-SI3. Eur J Med Chem. 2021 Jan 15;210:112966. DOI:10.1016/j.ejmech.2020.112966
[3] Kilpatrick BS, et al. Endo-lysosomal TRP mucolipin-1 channels trigger global ER Ca2+ release and Ca2+ influx. J Cell Sci. 2016 Oct 15;129(20):3859-3867. DOI:10.1242/jcs.190322
[4] Bais S, et al. Schistosome TRPML channels play a role in neuromuscular activity and tegumental integrity. Biochimie. 2022 Mar;194:108-117. DOI:10.1016/j.biochi.2021.12.018
[5] Zhang X, et al. Rapamycin directly activates lysosomal mucolipin TRP channels independent of mTOR. PLoS Biol. 2019 May 21;17(5):e3000252. DOI:10.1371/journal.pbio.3000252
[6] Xing Y, et al. Blunting TRPML1 channels protects myocardial ischemia/reperfusion injury by restoring impaired cardiomyocyte autophagy. Basic Res Cardiol. 2022 Apr 7;117(1):20. DOI:10.1007/s00395-022-00930-x

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