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MedKoo Cat#: 526681 | Name: Icilin
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Description:

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

Icilin is a synthetic super-agonist of the transient receptor potential M8 (TRPM8) ion channel. Although structurally not related with menthol it produces an extreme sensation of cold both in humans and animals. It is almost 200 times more potent than menthol and 2.5 times more efficacious. Despite their similar effects icilin activates the TRPM8 receptor in a different way. Icilin is effective in an experimental model of itch. It is now used as a research tool for the study of TRP channels.

Chemical Structure

Icilin
Icilin
CAS#36945-98-9

Theoretical Analysis

MedKoo Cat#: 526681

Name: Icilin

CAS#: 36945-98-9

Chemical Formula: C16H13N3O4

Exact Mass: 311.0906

Molecular Weight: 311.30

Elemental Analysis: C, 61.73; H, 4.21; N, 13.50; O, 20.56

Price and Availability

Size Price Availability Quantity
100mg USD 850.00 2 Weeks
200mg USD 1,450.00 2 Weeks
500mg USD 2,150.00 2 Weeks
1g USD 3,450.00 2 Weeks
2g USD 4,950.00 2 Weeks
5g USD 7,950.00 2 Weeks
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Related CAS #
No Data
Synonym
AG 3-5; AG3-5; AG-3-5; AG 3-5 cpd; BRN 0700310; Icilin.
IUPAC/Chemical Name
3,6-Dihydro-1-(2-hydroxyphenyl)-4-(3-nitrophenyl)-2(1H)-pyrimidinone
InChi Key
RCEFMOGVOYEGJN-UHFFFAOYSA-N
InChi Code
InChI=1S/C16H13N3O4/c20-15-7-2-1-6-14(15)18-9-8-13(17-16(18)21)11-4-3-5-12(10-11)19(22)23/h1-8,10,20H,9H2,(H,17,21)
SMILES Code
O=C1NC(C2=CC=CC([N+]([O-])=O)=C2)=CCN1C3=CC=CC=C3O
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
Instruction
View handling instruction
Biological target:
Icilin (AG-3-5) is a super-agonist of the transient receptor potential M8 (TRPM8) ion channel. Icilin activates TRPM8 in EGTA in a dose-dependent manner (EC50=1.4 μM).
In vitro activity:
Icilin, a known cooling substance and putative ligand of TRPM8, reversibly inhibits TRPV3 activity at nanomolar concentrations in expression systems like Xenopus laeves oocytes, HEK-293 cells, and in cultured human keratinocytes. These data show that icilin's antagonistic effects for the warm-sensitive TRPV3 ion channel occurs at very low concentrations. Therefore, the cooling effect evoked by icilin may at least in part be due to TRPV3 inhibition in addition to TRPM8 potentiation. Blockade of TRPV3 activity by icilin at such low concentrations might have important implications for overall cooling sensations detected by keratinocytes and free nerve endings in skin. Reference: Scientific World Journal. 2012;2012:982725. https://pubmed.ncbi.nlm.nih.gov/22548000/
In vivo activity:
The inhibitory effect of clonidine was both rapid in onset, as a significant attenuation (P < 0.05) of icilin-induced shaking in rats was observed 5 min post-clonidine injection, and persistent in duration, as it endured for the entire 35-min observation interval (fig. 3). Reference: Brain Res. 2011 Apr 12;1384:110-7. https://pubmed.ncbi.nlm.nih.gov/21315691/
Solvent mg/mL mM
Solubility
DMF 25.0 80.31
DMSO 36.7 117.93
DMSO:PBS (pH 7.2) (1:5) 0.1 0.32
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 311.30 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.

Recalculate based on batch purity %
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. Sherkheli MA, Gisselmann G, Hatt H. Supercooling agent icilin blocks a warmth-sensing ion channel TRPV3. Scientific World Journal. 2012;2012:982725. doi: 10.1100/2012/982725. Epub 2012 Apr 1. PMID: 22548000; PMCID: PMC3324214. 2. Chuang HH, Neuhausser WM, Julius D. The super-cooling agent icilin reveals a mechanism of coincidence detection by a temperature-sensitive TRP channel. Neuron. 2004 Sep 16;43(6):859-69. doi: 10.1016/j.neuron.2004.08.038. PMID: 15363396. 3. Kim J, Cowan A, Lisek R, Raymondi N, Rosenthal A, Hirsch DD, Rawls SM. Icilin-evoked behavioral stimulation is attenuated by alpha₂-adrenoceptor activation. Brain Res. 2011 Apr 12;1384:110-7. doi: 10.1016/j.brainres.2011.02.002. PMID: 21315691; PMCID: PMC3102431. 4. Rossi HL, Vierck CJ Jr, Caudle RM, Yezierski RP, Neubert JK. Dose-dependent effects of icilin on thermal preference in the hindpaw and face of rats. J Pain. 2009 Jun;10(6):646-53. doi: 10.1016/j.jpain.2009.01.002. Epub 2009 May 5. PMID: 19409862; PMCID: PMC2731548.
In vitro protocol:
1. Sherkheli MA, Gisselmann G, Hatt H. Supercooling agent icilin blocks a warmth-sensing ion channel TRPV3. Scientific World Journal. 2012;2012:982725. doi: 10.1100/2012/982725. Epub 2012 Apr 1. PMID: 22548000; PMCID: PMC3324214. 2. Chuang HH, Neuhausser WM, Julius D. The super-cooling agent icilin reveals a mechanism of coincidence detection by a temperature-sensitive TRP channel. Neuron. 2004 Sep 16;43(6):859-69. doi: 10.1016/j.neuron.2004.08.038. PMID: 15363396.
In vivo protocol:
1. Kim J, Cowan A, Lisek R, Raymondi N, Rosenthal A, Hirsch DD, Rawls SM. Icilin-evoked behavioral stimulation is attenuated by alpha₂-adrenoceptor activation. Brain Res. 2011 Apr 12;1384:110-7. doi: 10.1016/j.brainres.2011.02.002. PMID: 21315691; PMCID: PMC3102431. 2. Rossi HL, Vierck CJ Jr, Caudle RM, Yezierski RP, Neubert JK. Dose-dependent effects of icilin on thermal preference in the hindpaw and face of rats. J Pain. 2009 Jun;10(6):646-53. doi: 10.1016/j.jpain.2009.01.002. Epub 2009 May 5. PMID: 19409862; PMCID: PMC2731548.
1: De Petrocellis L, Ortar G, Schiano Moriello A, Serum EM, Rusterholz DB. Structure-activity relationships of the prototypical TRPM8 agonist icilin. Bioorg Med Chem Lett. 2015 Jun 1;25(11):2285-90. doi: 10.1016/j.bmcl.2015.04.032. Epub 2015 Apr 16. PubMed PMID: 25935641. 2: Hagenacker T, Lampe M, Schäfers M. Icilin reduces voltage-gated calcium channel currents in naïve and injured DRG neurons in the rat spinal nerve ligation model. Brain Res. 2014 Apr 4;1557:171-9. doi: 10.1016/j.brainres.2014.02.022. Epub 2014 Feb 18. PubMed PMID: 24560602. 3: Lee S, Chun JN, Kim SH, So I, Jeon JH. Icilin inhibits E2F1-mediated cell cycle regulatory programs in prostate cancer. Biochem Biophys Res Commun. 2013 Nov 29;441(4):1005-10. doi: 10.1016/j.bbrc.2013.11.015. Epub 2013 Nov 12. PubMed PMID: 24239550. 4: Selescu T, Ciobanu AC, Dobre C, Reid G, Babes A. Camphor activates and sensitizes transient receptor potential melastatin 8 (TRPM8) to cooling and icilin. Chem Senses. 2013 Sep;38(7):563-75. doi: 10.1093/chemse/bjt027. Epub 2013 Jul 4. PubMed PMID: 23828908. 5: Sherkheli MA, Gisselmann G, Hatt H. Supercooling agent icilin blocks a warmth-sensing ion channel TRPV3. ScientificWorldJournal. 2012;2012:982725. doi: 10.1100/2012/982725. Epub 2012 Apr 1. PubMed PMID: 22548000; PubMed Central PMCID: PMC3324214. 6: Vladymyrova IA, Filippov IB, Kuliieva IeM, Iurkevych A, Skryma R, Prevarskaia N, Shuba IaM. [Comparative effects of menthol and icilin on the induced contraction of the smooth muscles of the vas deferens of normal and castrated rats]. Fiziol Zh. 2011;57(4):21-33. Ukrainian. PubMed PMID: 22164406. 7: Han JH, Choi HK, Kim SJ. Topical TRPM8 agonist (icilin) relieved vulva pruritus originating from lichen sclerosus et atrophicus. Acta Derm Venereol. 2012 Sep;92(5):561-2. doi: 10.2340/00015555-1244. PubMed PMID: 22042233. 8: Wu SN, Wu PY, Tsai ML. Characterization of TRPM8-like channels activated by the cooling agent icilin in the macrophage cell line RAW 264.7. J Membr Biol. 2011 May;241(1):11-20. doi: 10.1007/s00232-011-9358-6. Epub 2011 Mar 29. PubMed PMID: 21445583. 9: Kim J, Cowan A, Lisek R, Raymondi N, Rosenthal A, Hirsch DD, Rawls SM. Icilin-evoked behavioral stimulation is attenuated by alpha₂-adrenoceptor activation. Brain Res. 2011 Apr 12;1384:110-7. doi: 10.1016/j.brainres.2011.02.002. PubMed PMID: 21315691; PubMed Central PMCID: PMC3102431. 10: Kim SH, Kim SY, Park EJ, Kim J, Park HH, So I, Kim SJ, Jeon JH. Icilin induces G1 arrest through activating JNK and p38 kinase in a TRPM8-independent manner. Biochem Biophys Res Commun. 2011 Mar 4;406(1):30-5. doi: 10.1016/j.bbrc.2011.01.094. Epub 2011 Feb 1. PubMed PMID: 21284938. 11: Anand U, Otto WR, Anand P. Sensitization of capsaicin and icilin responses in oxaliplatin treated adult rat DRG neurons. Mol Pain. 2010 Nov 24;6:82. doi: 10.1186/1744-8069-6-82. PubMed PMID: 21106058; PubMed Central PMCID: PMC3003244. 12: Kayano T, Kitamura N, Moriya T, Tsutsumi A, Ozaki Y, Dayanithi G, Shibuya I. Chronic treatment with NGF induces spontaneous fluctuations of intracellular Ca(2+) in icilin-sensitive dorsal root ganglion neurons of the rat. J Vet Med Sci. 2010 Dec;72(12):1531-8. Epub 2010 Jul 20. PubMed PMID: 20657161. 13: Ma S. Letter to the editor: "Is menthol- or icilin-induced vasodilation mediated by the activation of TRPM8?". Am J Physiol Heart Circ Physiol. 2009 Aug;297(2):H887; author reply H888. doi: 10.1152/ajpheart.00460.2009. PubMed PMID: 19635848. 14: Rossi HL, Vierck CJ Jr, Caudle RM, Yezierski RP, Neubert JK. Dose-dependent effects of icilin on thermal preference in the hindpaw and face of rats. J Pain. 2009 Jun;10(6):646-53. doi: 10.1016/j.jpain.2009.01.002. Epub 2009 May 5. PubMed PMID: 19409862; PubMed Central PMCID: PMC2731548. 15: Werkheiser J, Cowan A, Gomez T, Henry C, Parekh S, Chau S, Baron DA, Rawls SM. Icilin-induced wet-dog shakes in rats are dependent on NMDA receptor activation and nitric oxide production. Pharmacol Biochem Behav. 2009 May;92(3):543-8. doi: 10.1016/j.pbb.2009.02.005. Epub 2009 Feb 25. PubMed PMID: 19248800. 16: Kühn FJ, Kühn C, Lückhoff A. Inhibition of TRPM8 by icilin distinct from desensitization induced by menthol and menthol derivatives. J Biol Chem. 2009 Feb 13;284(7):4102-11. doi: 10.1074/jbc.M806651200. Epub 2008 Dec 18. PubMed PMID: 19095656. 17: Ito S, Kume H, Shiraki A, Kondo M, Makino Y, Kamiya K, Hasegawa Y. Inhibition by the cold receptor agonists menthol and icilin of airway smooth muscle contraction. Pulm Pharmacol Ther. 2008 Oct;21(5):812-7. doi: 10.1016/j.pupt.2008.07.001. Epub 2008 Jul 5. PubMed PMID: 18647657. 18: Brignell JL, Chapman V, Kendall DA. Comparison of icilin- and cold-evoked responses of spinal neurones, and their modulation of mechanical activity, in a model of neuropathic pain. Brain Res. 2008 Jun 18;1215:87-96. doi: 10.1016/j.brainres.2008.03.072. Epub 2008 Apr 9. PubMed PMID: 18479674. 19: Ding Z, Gomez T, Werkheiser JL, Cowan A, Rawls SM. Icilin induces a hyperthermia in rats that is dependent on nitric oxide production and NMDA receptor activation. Eur J Pharmacol. 2008 Jan 14;578(2-3):201-8. Epub 2007 Oct 3. PubMed PMID: 17976579. 20: Rawls SM, Gomez T, Ding Z, Raffa RB. Differential behavioral effect of the TRPM8/TRPA1 channel agonist icilin (AG-3-5). Eur J Pharmacol. 2007 Dec 1;575(1-3):103-4. Epub 2007 Aug 3. PubMed PMID: 17765220.