RQ-00203078 | CAS#1254205-52-1 | TRPM8 antagonist

MedKoo Cat#: 407141 | Name: RQ-00203078

Description:

WARNING: This product is for research use only, not for human or veterinary use.

RQ-00203078 is a potent, selective and orally active TRPM8 antagonist (IC50 values are 5.3 and 8.3 nM for rat and human channels respectively). RQ-00203078 blocks TRPM8 activity and reduces the invasion potential of oral squamous carcinoma cell lines. RQ-00203078 (RQ) profoundly reduced such agonist-induced cation currents. TRPM8 is reportedly an important player in carcinogenesis in human prostate cancer. 6).

Chemical Structure

RQ-00203078

CAS#1254205-52-1

Theoretical Analysis

MedKoo Cat#: 407141

Name: RQ-00203078

CAS#: 1254205-52-1

Chemical Formula: C21H13ClF6N2O5S

Exact Mass: 554.0138

Molecular Weight: 554.84

Elemental Analysis: C, 45.46; H, 2.36; Cl, 6.39; F, 20.54; N, 5.05; O, 14.42; S, 5.78

Price and Availability

Size	Price	Availability
10mg	USD 90.00	Ready to ship
25mg	USD 150.00	Ready to ship
50mg	USD 250.00	Ready to ship
100mg	USD 450.00	Ready to ship
200mg	USD 750.00	Ready to ship
500mg	USD 1,250.00	Ready to ship
1g	USD 2,150.00	Ready to ship
2g	USD 3,850.00	Ready to ship
5g	USD 5,850.00	Ready to ship

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Related CAS #

No Data

Synonym

RQ-00203078; RQ 00203078; RQ00203078.

IUPAC/Chemical Name

4-(N-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-(trifluoromethoxy)benzyl)sulfamoyl)benzoic acid

InChi Key

IJGQFZYYEHCCIZ-UHFFFAOYSA-N

InChi Code

InChI=1S/C21H13ClF6N2O5S/c22-17-9-14(20(23,24)25)10-29-18(17)30(11-12-1-5-15(6-2-12)35-21(26,27)28)36(33,34)16-7-3-13(4-8-16)19(31)32/h1-10H,11H2,(H,31,32)

SMILES Code

O=C(O)C1=CC=C(S(=O)(N(C2=NC=C(C(F)(F)F)C=C2Cl)CC3=CC=C(OC(F)(F)F)C=C3)=O)C=C1

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#BBC60324

QC Data

View QC data: current batch, Lot#BBC60324

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

RQ-00203078 is a highly selective TRPM8 antagonist with IC50s of 5.3 nM and 8.3 nM for rat and human TRPM8 channels, respectively as well as shows little inhibitory action against TRPV1, TRPA1, TRPV4, or TRPM2 channels.

In vitro activity:

To examine which types of TRP channels might be present in carcinoma cell lines derived from the human tongue, RT-PCR was performed using total RNA extracted from HSC3 and HSC4 cells by means of pairs of primers designed to recognize the mRNA of several TRP members (Table I). To try to determine whether TRPM8 is involved in the menthol-induced response, RQ (RQ00203078 ) (10 µM) was used, a selective antagonist of TRPM8 (11). RQ completely inhibited thementhol-induced current (Fig. 2A). In HSC3 cells, RQ virtually abolished the response to menthol at all voltage steps within the range -100 to 100 mV. Both the menthol-induced effect and the WS-12-induced effect were significantly inhibited by RQ at either membrane potential in a concentration-dependent manner (1-10 µM). In addition to their sensitivity to menthol, HSC3 cells were sensitive to cooling (Fig. 2E). When the temperature of the external solution was decreased from 26˚C to 17˚C, the basal inward current recorded at -50 mV was progressively enhanced, and this effect was reversed in the presence of RQ. These results suggest that RQ is able to discriminate between the two classes of cold-sensing channels. Notably, the continued presence of RQ significantly attenuated both the mentholinduced [Ca2+]I elevation associated with intracellular Ca2+ release and the menthol-induced store-operated Ca2+ entry (open circles in Fig. 5A and B). These results suggest that intracellular TRPM8 channels function as Ca2+-release ER channels, and that these are sensitive to RQ. In the serum-free condition, menthol significantly increased migration in both cell types, while RQ significantly decreased the migration distance (both in the presence and absence of menthol) to a level below the migration distance measured in the control condition. These results suggest the involvement of both menthol-activated and basally activated TRPM8 in such RQblockable cell motility. RQ also suppressed the MMP-9 activity seen in the presence of menthol (Fig. 9A and B). The present study clearly demonstrates that RQ has a potent inhibitory effect on TRPM8-mediated responses associated with both the plasma membrane and ER channels. Reference: Int J Oncol. 2012 May;40(5):1431-40. https://pubmed.ncbi.nlm.nih.gov/22267123/

In vivo activity:

To verify that the TRPM8 channel mediated morphine induced cold hyperalgesia, RQ-00203078, a selective antagonist of TRPM8, was administed to both morphine treated and saline control rats. A dose of 3 mg/kg (i.p) RQ-00203078 blocked the cold plate induced paw lifts in both groups. In the morphine treated group, the antagonist reduced the number of paw lifts from 13.1 ± 2.5 to 2.2 ± 0.9 (p < 0.01, n = 8, Fig. 3). In the saline treated group, the number of paw lifts was reduced from 2.9 ± 1.1 to 0.6 ± 0.3 (p < 0.01, n = 9). Sustained morphine administration also induced mechanical hyperalgesia as determined by the response to von Frey hair stimulus (p < 0.01, n = 7, supplementary Fig. S2). Therefore the mechanical threshold was used to determine if RQ-00203078 blocked behaviors other than the cold behavior. In saline treated rats, administration of RQ-00203078 did not affect withdrawal from the mechanical stimulus, which was 25.4 ± 2.1 g (pre-administration) and 26.9 ± 2.2 g (post-administration) respectively (p > 0.05). Similarly, administration of RQ-00203078 did not have any significant effect on mechanosensitivity in morphine treated rats. The threshold was 16.9 ± 2.4 g before RQ-00203078 and 16.1 ± 2.5 g after RQ-00203078 (supplementary Fig. S2). Therefore, RQ-00203078 selectively blocked cold hyperalgesia without affecting mechanical hyperalgesia in morphine treated rats. Reference: J Pain. 2017 Feb; 18(2): 212–221. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291755/

	Solvent	mg/mL	mM
Solubility
	DMSO	40.0	72.09
	H20	40.0	72.09

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 554.84 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Okamoto Y, Ohkubo T, Ikebe T, Yamazaki J. Blockade of TRPM8 activity reduces the invasion potential of oral squamous carcinoma cell lines. Int J Oncol. 2012 May;40(5):1431-40. doi: 10.3892/ijo.2012.1340. Epub 2012 Jan 20. PMID: 22267123. 2. Gong K, Jasmin L. Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia. J Pain. 2017 Feb;18(2):212-221. doi: 10.1016/j.jpain.2016.10.015. Epub 2016 Nov 12. PMID: 27845197; PMCID: PMC5291755. 3. Harrison E, Biswas L, Avusula R, Zhang M, Gong Y, Liu X. Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats. Psychopharmacology (Berl). 2017 Dec;234(23-24):3443-3453. doi: 10.1007/s00213-017-4736-0. Epub 2017 Sep 16. PMID: 28918457; PMCID: PMC5693741.

In vitro protocol:

In vivo protocol:

1. Gong K, Jasmin L. Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia. J Pain. 2017 Feb;18(2):212-221. doi: 10.1016/j.jpain.2016.10.015. Epub 2016 Nov 12. PMID: 27845197; PMCID: PMC5291755. 2. Harrison E, Biswas L, Avusula R, Zhang M, Gong Y, Liu X. Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats. Psychopharmacology (Berl). 2017 Dec;234(23-24):3443-3453. doi: 10.1007/s00213-017-4736-0. Epub 2017 Sep 16. PMID: 28918457; PMCID: PMC5693741.

1: Su L, Bai X, Niu T, Zhuang X, Dong B, Li Y, Yu Y, Wang G. P2Y1 Purinergic Receptor Contributes to Remifentanil-Induced Cold Hyperalgesia via Transient Receptor Potential Melastatin 8-Dependent Regulation of N-methyl-d-aspartate Receptor Phosphorylation in Dorsal Root Ganglion. Anesth Analg. 2021 Sep 1;133(3):794-810. doi: 10.1213/ANE.0000000000005617. PMID: 34166321. 2: Scheuble J, Rössler OG, Ulrich M, Thiel G. Pharmacological and genetic inhibition of TRPC6-induced gene transcription. Eur J Pharmacol. 2020 Nov 5;886:173357. doi: 10.1016/j.ejphar.2020.173357. Epub 2020 Aug 3. PMID: 32758574. 3: Ulrich M, Wissenbach U, Thiel G. The super-cooling compound icilin stimulates c-Fos and Egr-1 expression and activity involving TRPM8 channel activation, Ca2+ ion influx and activation of the ternary complex factor Elk-1. Biochem Pharmacol. 2020 Jul;177:113936. doi: 10.1016/j.bcp.2020.113936. Epub 2020 Mar 26. PMID: 32224140. 4: Thiel G, Backes TM, Welck J, Steinhausen S, Fischer AL, Langfermann DS, Ulrich M, Wissenbach U, Rössler OG. Pharmacological inhibition of TRPM8-induced gene transcription. Biochem Pharmacol. 2019 Dec;170:113678. doi: 10.1016/j.bcp.2019.113678. Epub 2019 Oct 22. PMID: 31654626. 5: Pfanzagl B, Pfragner R, Jensen-Jarolim E. The Transient Receptor Potential Vanilloid 4 Agonist RN-1747 Inhibits the Calcium Response to Histamine. Pharmacology. 2019;104(3-4):166-172. doi: 10.1159/000501144. Epub 2019 Jun 18. PMID: 31212298. 6: Harrison E, Biswas L, Avusula R, Zhang M, Gong Y, Liu X. Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats. Psychopharmacology (Berl). 2017 Dec;234(23-24):3443-3453. doi: 10.1007/s00213-017-4736-0. Epub 2017 Sep 16. PMID: 28918457; PMCID: PMC5693741. 7: Su L, Shu R, Song C, Yu Y, Wang G, Li Y, Liu C. Downregulations of TRPM8 expression and membrane trafficking in dorsal root ganglion mediate the attenuation of cold hyperalgesia in CCI rats induced by GFRα3 knockdown. Brain Res Bull. 2017 Oct;135:8-24. doi: 10.1016/j.brainresbull.2017.08.002. Epub 2017 Sep 1. PMID: 28867384. 8: Gong K, Jasmin L. Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia. J Pain. 2017 Feb;18(2):212-221. doi: 10.1016/j.jpain.2016.10.015. Epub 2016 Nov 12. PMID: 27845197; PMCID: PMC5291755. 9: Ito H, Aizawa N, Sugiyama R, Watanabe S, Takahashi N, Tajimi M, Fukuhara H, Homma Y, Kubota Y, Andersson KE, Igawa Y. Functional role of the transient receptor potential melastatin 8 (TRPM8) ion channel in the urinary bladder assessed by conscious cystometry and ex vivo measurements of single-unit mechanosensitive bladder afferent activities in the rat. BJU Int. 2016 Mar;117(3):484-94. doi: 10.1111/bju.13225. Epub 2015 Aug 16. PMID: 26189966. 10: Ohmi M, Shishido Y, Inoue T, Ando K, Fujiuchi A, Yamada A, Watanabe S, Kawamura K. Identification of a novel 2-pyridyl-benzensulfonamide derivative, RQ-00203078, as a selective and orally active TRPM8 antagonist. Bioorg Med Chem Lett. 2014 Dec 1;24(23):5364-8. doi: 10.1016/j.bmcl.2014.10.074. Epub 2014 Oct 29. PMID: 25455182. 11: Okamoto Y, Ohkubo T, Ikebe T, Yamazaki J. Blockade of TRPM8 activity reduces the invasion potential of oral squamous carcinoma cell lines. Int J Oncol. 2012 May;40(5):1431-40. doi: 10.3892/ijo.2012.1340. Epub 2012 Jan 20. PMID: 22267123. 12: Al-Shamahi A, Kirkham K, Hookes L. Society for Neuroscience - 39th Annual Meeting. Part 1 - Novel therapies for the treatment of CNS disorders and pain. IDrugs. 2009 Dec;12(12):731-3. PMID: 19943210.