RN 1734

Selective TRPV4 antagonist CAS# 946387-07-1

RN 1734

Catalog No. BCC7770----Order now to get a substantial discount!

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Chemical structure

RN 1734

3D structure

Chemical Properties of RN 1734

Cas No. 946387-07-1 SDF Download SDF
PubChem ID 3601086 Appearance Powder
Formula C14H22Cl2N2O2S M.Wt 353.31
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 50 mg/mL (141.52 mM; Need ultrasonic)
Chemical Name 2,4-dichloro-N-propan-2-yl-N-[2-(propan-2-ylamino)ethyl]benzenesulfonamide
SMILES CC(C)NCCN(C(C)C)S(=O)(=O)C1=C(C=C(C=C1)Cl)Cl
Standard InChIKey IHYZMEAZAIFMTN-UHFFFAOYSA-N
Standard InChI 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
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of RN 1734

DescriptionSelective TRPV4 antagonist (IC50 values are 2.3, 3.2 and 5.9 μM for hTRPV4, rTRPV4 and mTRPV4 receptors respectively). Displays selectivity for TRPV4 over other TRP channels (IC50 values are 2.3, >30, >30 and >100 μM for TRPV4, TRPV3, TRPM8 and TRPV1 respectively). Blocks TRPV4-mediated arteriole vasodilation and increases myogenic tone ex vivo.

RN 1734 Dilution Calculator

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Preparing Stock Solutions of RN 1734

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.8304 mL 14.1519 mL 28.3038 mL 56.6075 mL 70.7594 mL
5 mM 0.5661 mL 2.8304 mL 5.6608 mL 11.3215 mL 14.1519 mL
10 mM 0.283 mL 1.4152 mL 2.8304 mL 5.6608 mL 7.0759 mL
50 mM 0.0566 mL 0.283 mL 0.5661 mL 1.1322 mL 1.4152 mL
100 mM 0.0283 mL 0.1415 mL 0.283 mL 0.5661 mL 0.7076 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on RN 1734

RN-1734 is selective antagonist of the TRPV4 channel, completely antagonizes 4αPDD-mediated activation of TRPV4 with comparable, low micromolar IC50values for all three species (hTRPV4: IC50 = 2.3 μM, mTRPV4: IC50 = 5.9 μM, rTRPV4: IC50 = 3.2 μM). IC50 value: 2.3 μM (hTRPV4), 5.9 μM (mTRPV4), IC50 = 3.2 μM (rTRPV4) Target: TRPV4 in vitro: RN-1734 completely inhibits both ligand- and hypotonicity-activated TRPV4. In addition, RN-1734 is selective for TRPV4 in a TRP selectivity panel including TRPV1, TRPV3 and TRPM8, and could thus be a valuable pharmacological probe for TRPV4 studies. [1]

References:
[1]. Kato K, et al. 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- [2]. Vincent F, et al. Identification and characterization of novel TRPV4 modulators. Biochem Biophys Res Commun. 2009 Nov 20;389(3):490-4.

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References on RN 1734

Fatty acid amide hydrolase (FAAH) inhibitor PF-3845 reduces viability, migration and invasiveness of human colon adenocarcinoma Colo-205 cell line: an in vitro study.[Pubmed:28850633]

Acta Biochim Pol. 2017;64(3):519-525.

Earlier reports suggest that the endocannabinoids may play a role of endogenous tumor growth modulators. In this study, we investigated whether inhibition of the enzymes involved in the synthesis and degradation of endocannabinoids may reduce colorectal cancer cell invasion and migration. The human colon adenocarcinoma Colo-205 cells were incubated with PF-3845, JZL-184 and RHC-80267 (fatty acid amide hydrolase (FAAH), mono- (MAGL) and diacylglycerol lipase (DAGL) inhibitors, respectively) for 48 h. The MTT colorimetric assay was performed to quantify cell viability. Next, Colo-205 cells were incubated with PF-3845 alone or with PF-3845 together with selected antagonists: AM 251, AM 630, SB 366791, RN 1734 and G-15 (CB1, CB2, TRPV1, TRPV4 and GPR30 antagonists, respectively). Western blot assay was applied to identify the changes in CB1 and CB2 receptor expression. Migration and invasion assays were employed to characterize the effect of PF-3845 on colorectal cancer cell invasion. We found that of all the inhibitors used, the FAAH inhibitor PF-3845 reduced the Colo-205 cell line viability the most effectively (IC50=52.55 muM). We also showed that the effect of decreased cell viability was enhanced when Colo-205 cells were incubated with PF-3845 and RN-1734, a TRPV4 antagonist (IC50=30.54 muM). Western blot assay revealed significantly decreased CB1 receptor expression levels, while CB2 expression was increased in response to PF-3845 when compared to control. Furthermore, PF-3845 inhibited migration and invasion of Colo-205 cell line. These results suggest that pharmacological inhibition of FAAH and consequent enhancement of the endocannabinoid levels may reduce the colorectal cancer growth and progression.

TRPV4 channels contribute to renal myogenic autoregulation in neonatal pigs.[Pubmed:28768667]

Am J Physiol Renal Physiol. 2017 Nov 1;313(5):F1136-F1148.

Myogenic response, a phenomenon in which resistance size arteries and arterioles swiftly constrict or dilate in response to an acute elevation or reduction, respectively, in intravascular pressure is a key component of renal autoregulation mechanisms. Although it is well established that the renal system is functionally immature in neonates, mechanisms that regulate neonatal renal blood flow (RBF) remain poorly understood. In this study, we investigated the hypothesis that members of the transient receptor potential vanilloid (TRPV) channels are molecular components of renal myogenic constriction in newborns. We show that unlike TRPV1-3, TRPV4 channels are predominantly expressed in neonatal pig preglomerular vascular smooth muscle cells (SMCs). Intracellular Ca(2+) concentration ([Ca(2+)]i) elevation induced by osmotic cell swelling was attenuated by TRPV4, L-type Ca(2+), and stretch-activated Ca(2+) channel blockers but not phospholipase A2 inhibitor. Blockade of TRPV4 channels reversed steady-state myogenic tone and inhibited pressure-induced membrane depolarization, [Ca(2+)]i elevation, and constriction in distal interlobular arteries. A step increase in arterial pressure induced efficient autoregulation of renal cortical perfusion and total RBF in anesthetized and mechanically ventilated neonatal pigs. Moreover, intrarenal arterial infusion of the TRPV4 channel blockers HC 067047 and RN 1734 attenuated renal autoregulation in the pigs. These data suggest that renal myogenic autoregulation is functional in neonates. Our findings also indicate that TRPV4 channels are mechanosensors in neonatal pig preglomerular vascular SMCs and contribute to renal myogenic autoregulation.

Detection of TRPV4 channel current-like activity in Fawn Hooded hypertensive (FHH) rat cerebral arterial muscle cells.[Pubmed:28472069]

PLoS One. 2017 May 4;12(5):e0176796.

The transient receptor potential vallinoid type 4 (TRPV4) is a calcium entry channel known to modulate vascular function by mediating endothelium-dependent vasodilation. The present study investigated if isolated cerebral arterial myocytes of the Fawn Hooded hypertensive (FHH) rat, known to display exaggerated KCa channel current activity and impaired myogenic tone, express TRPV4 channels at the transcript and protein level and exhibit TRPV4-like single-channel cationic current activity. Reverse transcription polymerase chain reaction (RT-PCR), Western blot, and immunostaining analysis detected the expression of mRNA transcript and translated protein of TRPV4 channel in FHH rat cerebral arterial myocytes. Patch clamp recording of single-channel current activity identified the presence of a single-channel cationic current with unitary conductance of ~85 pS and ~96 pS at hyperpolarizing and depolarizing potentials, respectively, that was inhibited by the TRPV4 channel antagonist RN 1734 or HC 067074 and activated by the potent TRPV4 channel agonist GSK1016790A. Application of negative pressure via the interior of the patch pipette increased the NPo of the TRPV4-like single-channel cationic current recorded in cell-attached patches at a patch potential of 60 mV that was inhibited by prior application of the TRPV4 channel antagonist RN 1734 or HC 067047. Treatment with the TRPV4 channel agonist GSK1016790A caused concentration-dependent increase in the NPo of KCa single-channel current recorded in cell-attached patches of cerebral arterial myocytes at a patch potential of 40 mV, which was not influenced by pretreatment with the voltage-gated L-type Ca2+ channel blocker nifedipine or the T-type Ca2+ channel blocker Ni2+. These findings demonstrate that FHH rat cerebral arterial myocytes express mRNA transcript and translated protein for TRPV4 channel and display TRPV4-like single-channel cationic current activity that was stretch-sensitive and activation of which increased the open state probability of KCa single-channel current in these arterial myocytes.

Low intravascular pressure activates endothelial cell TRPV4 channels, local Ca2+ events, and IKCa channels, reducing arteriolar tone.[Pubmed:23071308]

Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):18174-9.

Endothelial cell (EC) Ca(2+)-activated K channels (SK(Ca) and IK(Ca) channels) generate hyperpolarization that passes to the adjacent smooth muscle cells causing vasodilation. IK(Ca) channels focused within EC projections toward the smooth muscle cells are activated by spontaneous Ca(2+) events (Ca(2+) puffs/pulsars). We now show that transient receptor potential, vanilloid 4 channels (TRPV4 channels) also cluster within this microdomain and are selectively activated at low intravascular pressure. In arterioles pressurized to 80 mmHg, ECs generated low-frequency (~2 min(-1)) inositol 1,4,5-trisphosphate receptor-based Ca(2+) events. Decreasing intraluminal pressure below 50 mmHg increased the frequency of EC Ca(2+) events twofold to threefold, an effect blocked with the TRPV4 antagonist RN1734. These discrete events represent both TRPV4-sparklet- and nonsparklet-evoked Ca(2+) increases, which on occasion led to intracellular Ca(2+) waves. The concurrent vasodilation associated with increases in Ca(2+) event frequency was inhibited, and basal myogenic tone was increased, by either RN1734 or TRAM-34 (IK(Ca) channel blocker), but not by apamin (SK(Ca) channel blocker). These data show that intraluminal pressure influences an endothelial microdomain inversely to alter Ca(2+) event frequency; at low pressures the consequence is activation of EC IK(Ca) channels and vasodilation, reducing the myogenic tone that underpins tissue blood-flow autoregulation.

Identification and characterization of novel TRPV4 modulators.[Pubmed:19737537]

Biochem Biophys Res Commun. 2009 Nov 20;389(3):490-4.

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.

Description

RN-1734 is selective antagonist of the TRPV4 channel, completely antagonizes 4αPDD-mediated activation of TRPV4 with comparable, low micromolar IC50s for all three species (hTRPV4: 2.3 μM, mTRPV4: 5.9 μM, rTRPV4: 3.2 μM). RN-1734 clearly decreases the production of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) without altering the number of olig2-positive cells.

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