hTRPV4 (IC50 = 2.3 μM); mTRPV4 (IC50 = 5.9 μM); rTRPV4 (IC50 = 3.2 μM)[1]

The increase in astrocyte fluorescence rate caused by CM (LPS-activated astrocyte group) cell fluorescence can be reversed by RN-1734 (27 hours; 10 μM) [2]. 10 μM; RN-1734 (27).

RN-1734 (0.5 μL; microinjection pump; once daily for 5 weeks) dramatically reverses CNP cosmetology and repairs myelination in the CPZ-induced demyelination mouse [2].

TRPV4, a close relative of the vanilloid receptor TRPV1, is activated by diverse modalities such as endogenous lipid ligands, hypotonicity, protein kinases and, possibly, mechanical inputs. While its multiple roles in vivo are being explored with KO mice and selective agonists, there is a dearth of selective antagonists available to examine TRPV4 function. Herein we detail the use of a focused library of commercial compounds in order to identify RN-1747 and RN-1734, a pair of structurally related small molecules endowed with TRPV4 agonist and antagonist properties, respectively. Their activities against human, rat and mouse TRPV4 were characterized using electrophysiology and intracellular calcium influx. Significantly, antagonist RN-1734 was observed to completely inhibit both ligand- and hypotonicity-activated TRPV4. In addition, RN-1734 was found to be selective for TRPV4 in a TRP selectivity panel including TRPV1, TRPV3 and TRPM8, and could thus be a valuable pharmacological probe for TRPV4 studies[3].

Apoptosis analysis [2]
Cell Types: Microglia
Tested Concentrations: 27 hrs (hours)
Incubation Duration: 10μM
Experimental Results: The percentage of cleaved-caspase 3 positive cells was Dramatically diminished. ) weakens the CM-induced CNP decrease [2].

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Western Blot Analysis[2]
Cell Types: Microglia
Tested Concentrations: 27 hrs (hours)
Incubation Duration: 10 μM
Experimental Results: Mitigation of CM (LPS only)-induced CNP decrease.

Animal/Disease Models: CPZ-induced demyelination mouse model (C57BL/6 male mice) [2]
Doses: 0.5 μl (10 μM, dissolved in 5% DMSO and 0.9% NaCl)
Route of Administration: Microinjection pump 5-week
Experimental Results: Dramatically reversed the decrease in CNP protein and improved myelination in CPZ-induced demyelination mice.

[1]. Acidosis environment promotes osteoclast formation by acting on the last phase of preosteoclast differentiation: a study to elucidate the action points of acidosis and search for putative target molecules. Eur J Pharmacol. 2011 Aug 1;663(1-3):27-39.

[2]. TRPV4 Inhibition Improved Myelination and Reduced Glia Reactivity and Inflammation in a Cuprizone-Induced Mouse Model of Demyelination. Front Cell Neurosci. 2018 Nov 5;12:392.

[3]. Identification and characterization of novel TRPV4 modulators. Biochem Biophys Res Commun. 2009 Nov 20;389(3):490-4.

Acidosis promoted tartaric acid-resistant acid phosphatase-positive multinuclear cell (TRAP+MNC) or osteoclast formation. Large osteoclast or TRAP+LMNC formation was observed far more in an acidosis environment than in a physiologically neutral environment. One of the major action points of acidosis was determined to be located in the last phase of preosteoclast differentiation using a co-culture system and a soluble RANKL-dependent bone marrow cell culture system. On-going osteoclast formation in an acidosis environment markedly deteriorated when the medium was replaced with physiologically neutral medium within the first 6h; however, bone marrow cells previously stimulated in an acidosis environment for 9h differentiated into TRAP+LMNC in pH 7.4 medium. Messenger RNA (mRNA) expression levels of DC-STAMP, a key molecule in cell fusion, and NFATc1 did not increase in the acidosis environment compared with those under physiologically neutral conditions. Ruthenium red, a general TRP antagonist, deteriorated acidosis-promoted TRAP+LMNC formation. 4-Alpha-PDD, a TRPV4-specific agonist, added in the last 21 h of preosteoclast differentiation, potentiated TRAP+LMNC formation in a mild acidosis environment, showing synergism between TRPV4 activation and acidosis. RN1734, a TRPV4-specific antagonist, partly inhibited acidosis-promoted TRAP+LMNC formation. We thus narrowed down the major action points of acidosis in osteoclast formation and elucidated the characteristics of this system in detail. Our results show that acidosis effectively uses TRPV4 to drive large-scale cell fusion and also utilizes systems independently of TRPV4.[1]

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The inhibition of demyelination and the promotion of remyelination are both considerable challenges in the therapeutic process for many central nervous system (CNS) diseases. Increasing evidence has demonstrated that neuroglial activation and neuroinflammation are responsible for myelin sheath damage during demyelinating disorders. It has been revealed that the nonselective cation channel transient receptor potential vanilloid 4 (TRPV4) profoundly affects a variety of physiological processes, including inflammation. However, its roles and mechanisms in demyelination have remained unclear. Here, for the first time, we found that there was a significant increase in TRPV4 in the corpus callosum in a demyelinated mouse model induced by cuprizone (CPZ). RN-1734, a TRPV4-antagonist, clearly alleviated demyelination and inhibited glial activation and the production of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) without altering the number of olig2-positive cells. In vitro, RN-1734 treatment clearly inhibited the influx of calcium and decreased the levels of IL-1β and TNF-α in lipopolysaccharide (LPS)-activated microglial cells by suppressing NF-κB P65 phosphorylation. Apoptosis of oligodendrocyte induced by LPS-activated microglia was also alleviated by RN-1734. The results suggest that activation of TRPV4 in microglia is involved in oligodendrocyte apoptosis through the activation of the NF-κB signaling pathway, thus revealing a new mechanism of CNS demyelination.[2]

C14H22CL2N2O2S

353.3

352.078

946387-07-1

3601086

White to off-white solid powder

1.228g/cm3

445ºC at 760 mmHg

222.9ºC

1.536

4.862

1

4

7

21

410

0

O=S(N(C(C)C)CCNC(C)C)(C1C(Cl)=CC(Cl)=CC=1)=O

IHYZMEAZAIFMTN-UHFFFAOYSA-N

InChI=1S/C14H22Cl2N2O2S/c1-10(2)17-7-8-18(11(3)4)21(19,20)14-6-5-12(15)9-13(14)16/h5-6,9-11,17H,7-8H2,1-4H3

2,4-dichloro-N-(propan-2-yl)-N-{2-[(propan-2-yl)amino]ethyl}benzene-1-sulfonamide

RN-1734; RN 1734; 2,4-Dichloro-N-isopropyl-N-(2-isopropylaminoethyl)benzenesulfonamide; CHEMBL2324347; 2,4-dichloro-N-isopropyl-N-(2-(isopropylamino)ethyl)benzenesulfonamide; 2,4-dichloro-N-propan-2-yl-N-[2-(propan-2-ylamino)ethyl]benzenesulfonamide; RN1734.

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)

DMSO : ~25 mg/mL (~70.76 mM)

Solubility in Formulation 1: ≥ 3.25 mg/mL (9.20 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 32.5 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 3.25 mg/mL (9.20 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 32.5 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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Solubility in Formulation 3: ≥ 3.25 mg/mL (9.20 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 32.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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