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Curcumin
Curcumin
is a bright yellow chemical produced by some plants. It is the principal curcuminoid of turmeric (Curcuma longa), a member of the ginger family, Zingiberaceae. It is sold as an herbal supplement, cosmetics ingredient, food flavoring, and food coloring.[1] Chemically, curcumin is a diarylheptanoid, belonging to the group of curcuminoids, which are natural phenols responsible for turmeric's yellow color. It is a tautomeric compound existing in enolic form in organic solvents, and as a keto form in water.[2] Although thoroughly studied in laboratory and clinical studies, curcumin has no confirmed medical uses, and has proved frustrating to scientists because it is unstable, not bioavailable, and unlikely to produce useful leads for drug development.[3]

Contents

1 History 2 Uses 3 Chemistry

3.1 Biosynthesis

4 Pharmacology

4.1 Safety

5 Research 6 Alternative medicine 7 References 8 External links

History[edit] It was first isolated in 1815 when Vogel and Pierre Joseph Pelletier reported the isolation of a "yellow coloring-matter" from the rhizomes of turmeric and named it curcumin.[4] Although curcumin has been used historically in Ayurvedic medicine,[5] its potential for medicinal properties remains unproven as a therapy when used orally.[3][6][7] Uses[edit]

Curcumin
Curcumin
powder

The most common applications are as an ingredient in dietary supplement, in cosmetics, and as flavoring for foods, such as turmeric-flavored beverages in the Indian Subcontinent
Indian Subcontinent
and Southeast Asia.[1] As a food additive for gold-orange coloring in turmeric and prepared foods, its E number
E number
is E100.[8] Annual sales of curcumin have increased since 2012, largely due to an increase in its popularity.[1] It is present in skincare products that are marketed as containing natural ingredients or dyes, especially in Asia.[1] The largest market is in North America, where sales exceeded US$20 million in 2014.[1] Chemistry[edit]

Curcumin
Curcumin
becomes bright red when it interacts electrostatically with phospholipid film.

Curcumin
Curcumin
incorporates several functional groups whose structure was first identified in 1910.[9] The aromatic ring systems, which are phenols, are connected by two α,β-unsaturated carbonyl groups. The diketones form stable enols and are readily deprotonated to form enolates; the α,β-unsaturated carbonyl group is a good Michael acceptor and undergoes nucleophilic addition. Curcumin
Curcumin
is used as a complexometric indicator for boron.[10] It reacts with boric acid to form a red-colored compound, rosocyanine. Biosynthesis[edit] The biosynthetic route of curcumin is uncertain. In 1973, Roughly and Whiting proposed two mechanisms for curcumin biosynthesis. The first mechanism involves a chain extension reaction by cinnamic acid and 5 malonyl-CoA molecules that eventually arylized into a curcuminoid. The second mechanism involves two cinnamate units coupled together by malonyl-CoA. Both use cinnamic acid as their starting point, which is derived from the amino acid phenylalanine.[11] Plant biosyntheses starting with cinnamic acid is rare compared to the more common p-coumaric acid.[11] Only a few identified compounds, such as anigorufone and pinosylvin, build from cinnamic acid.[12][13]

Biosynthetic pathway of curcumin in Curcuma longa.[11]

Pharmacology[edit] Curcumin, which shows positive results in most drug discovery assays, is regarded as a false lead that medicinal chemists include among "pan-assay interference compounds" attracting undue experimental attention while failing to advance as viable therapeutic or drug leads.[3][6][14] In vitro, curcumin inhibits certain epigenetic enzymes (the histone deacetylases: HDAC1, HDAC3, HDAC8), transcriptional co-activator proteins (the p300 histone acetyltransferase)[15][16][17] and the arachidonate 5-lipoxygenase enzyme.[18] Factors that limit the bioactivity of curcumin or its analogs include chemical instability, water insolubility, absence of potent and selective target activity, low bioavailability, limited tissue distribution, extensive metabolism, and potential for toxicity.[3] Safety[edit] Two preliminary clinical studies in cancer patients consuming high doses of curcumin (up to 8 grams per day for 3–4 months) showed no toxicity, though some subjects reported mild nausea or diarrhea.[19] Research[edit] In vitro, curcumin exhibits numerous interference properties which may lead to misinterpretation of results.[3][6][20] Although curcumin has been assessed in numerous laboratory and clinical studies, it has no medical uses established by well-designed clinical research.[21] According to a 2017 review of over 120 studies, curcumin has not been successful in any clinical trial, leading the authors to conclude that "curcumin is an unstable, reactive, non-bioavailable compound and, therefore, a highly improbable lead".[3] Cancer studies using curcumin conducted by Bharat Aggarwal, formerly a researcher at the MD Anderson Cancer Center, were deemed fraudulent and subsequently retracted by the publisher.[22] Alternative medicine[edit] Despite concerns about safety or efficacy and the absence of reliable clinical research,[3][6] some alternative medicine practitioners give turmeric intravenously, supposedly as a treatment for numerous diseases.[23] In 2017 there were two serious cases of adverse events reported – one severe allergic reaction and one death – that were caused by injection of a curcumin emulsion product administered by a naturopath.[24][25] The US government has supported $150 million in research into curcumin through the National Center for Complementary and Integrative Health, and no support has been found for curcumin as a medical treatment.[25] References[edit]

^ a b c d e Majeed, Shaheen (28 December 2015). "The State of the Curcumin
Curcumin
Market". Natural Products Insider.  ^ Manolova Y, Deneva V, Antonov L, Drakalska E, Momekova D, Lambov N (2014). "The effect of the water on the curcumin tautomerism: A quantitative approach". Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 132: 815–820. doi:10.1016/j.saa.2014.05.096.  ^ a b c d e f g Nelson, K. M.; Dahlin, J. L.; Bisson, J.; Graham, J.; Pauli, G. F.; Walters, M. A. (2017). "The Essential Medicinal Chemistry of Curcumin: Miniperspective". Journal of Medicinal Chemistry. 60 (5): 1620–1637. doi:10.1021/acs.jmedchem.6b00975. PMC 5346970 . PMID 28074653.  ^ Vogel, H.; Pelletier, J. (1815). " Curcumin
Curcumin
–biological and medicinal properties". Journal de Pharmacie. I: 289.  ^ Wilken, Reason; Veena, Mysore S.; Wang, Marilene B.; Srivatsan, Eri S. (2011). "Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma". Molecular Cancer. 10: 12. doi:10.1186/1476-4598-10-12. ISSN 1476-4598. PMC 3055228 . PMID 21299897.  ^ a b c d Baker, Monya (9 January 2017). "Deceptive curcumin offers cautionary tale for chemists". Nature. 541 (7636): 144–145. doi:10.1038/541144a. PMID 28079090.  ^ "Turmeric". US National Center for Complementary and Integrative Health, National Institutes of Health. 31 May 2016. Retrieved 15 June 2016.  ^ European Commission. "Food Additives". Retrieved 2014-02-15.  ^ Miłobȩdzka, J.; van Kostanecki, S.; Lampe, V. (1910). "Zur Kenntnis des Curcumins". Berichte der deutschen chemischen Gesellschaft. 43 (2): 2163–2170. doi:10.1002/cber.191004302168.  ^ "EPA Method 212.3: Boron
Boron
(Colorimetric, Curcumin)" (PDF).  ^ a b c Kita, Tomoko; Imai, Shinsuke; Sawada, Hiroshi; Kumagai, Hidehiko; Seto, Haruo (2008). "The Biosynthetic Pathway of Curcuminoid in Turmeric
Turmeric
(Curcuma longa) as Revealed by 13C-Labeled Precursors". Bioscience, Biotechnology, and Biochemistry. 72 (7): 1789–1798. doi:10.1271/bbb.80075.  ^ Schmitt, Bettina; Hölscher, Dirk; Schneider, Bernd (2000). "Variability of phenylpropanoid precursors in the biosynthesis of phenylphenalenones in Anigozanthos preissii". Phytochemistry. 53 (3): 331–337. doi:10.1016/S0031-9422(99)00544-0. PMID 10703053.  ^ Gehlert, R.; Schoeppner, A.; Kindl, H. (1990). "Stilbene Synthase from Seedlings of Pinus sylvestris: Purification and Induction in Response to Fungal Infection" (pdf). Molecular Plant-Microbe Interactions. 3 (6): 444–449. doi:10.1094/MPMI-3-444.  ^ Bisson, Jonathan; McAlpine, James B.; Friesen, J. Brent; Chen, Shao-Nong; Graham, James; Pauli, Guido F. (2016-03-10). "Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery?". Journal of Medicinal Chemistry. 59 (5): 1671–1690. doi:10.1021/acs.jmedchem.5b01009. ISSN 0022-2623. PMC 4791574 . PMID 26505758.  ^ Reuter, S.; Gupta, S. C.; Park, B.; Goel, A.; Aggarwal, B. B. (May 2011). " Epigenetic
Epigenetic
changes induced by curcumin and other natural compounds". Genes & Nutrition. 6 (2): 93–108. doi:10.1007/s12263-011-0222-1. PMC 3092901 . PMID 21516481.  ^ Vahid, F.; Zand, H.; Nosrat-Mirshekarlou, E.; Najafi, R.; Hekmatdoost, A. (May 2015). "The role dietary of bioactive compounds on the regulation of histone acetylases and deacetylases: a review". Gene. 562 (1): 8–15. doi:10.1016/j.gene.2015.02.045. PMID 25701602.  ^ "Curcumin". IUPHAR. IUPHAR/BPS Guide to PHARMACOLOGY. Retrieved 22 May 2015.  ^ Bishayee, K.; Khuda-Bukhsh, A. R. (September 2013). "5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy". Acta Biochimica et Biophysica Sinica. Shanghai. 45 (9): 709–719. doi:10.1093/abbs/gmt064. PMID 23752617.  ^ Hsu, C. H.; Cheng, A. L. (2007). "Clinical studies with curcumin". Advances in Experimental Medicine and Biology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY. 595: 471–480. doi:10.1007/978-0-387-46401-5_21. ISBN 978-0-387-46400-8. PMID 17569225.  ^ Lowe, Derek (12 January 2017). " Curcumin
Curcumin
Will Waste Your Time". In the Pipeline.  ^ "Curcumin". Micronutrient Information Center; Phytochemicals. Linus Pauling Institute, Oregon State University, Corvallis. 2016. Retrieved 18 June 2016.  ^ Ackerman, T. (29 February 2012). "M.D. Anderson professor under fraud probe". Houston Chronicle. Retrieved 8 March 2016.  ^ Hermes, Britt Marie (27 March 2017). "Naturopathic Doctors Look Bad After California Woman Dies From Turmeric
Turmeric
Injection". Forbes. Retrieved 12 May 2017.  ^ "FDA investigates two serious adverse events associated with ImprimisRx's compounded curcumin emulsion product for injection". Food and Drug Administration. 4 August 2017.  ^ a b Hermes, Britt Marie (April 10, 2017). "Confirmed: Licensed Naturopathic Doctor Gave Lethal 'Turmeric' Injection". Forbes. Retrieved December 9, 2017. 

External links[edit]

Turmeric
Turmeric
and curcumin, from Memorial Sloan-Kettering Cancer Center

v t e

Curcuminoids

1,7-Bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one Bisdemethoxycurcumin Curcumin Desmethoxycurcumin Dimethylcurcumin

Curcuminoid
Curcuminoid
dyes

Rosocyanine Rubrocurcumin

v t e

Histone deacetylase inhibitors

3,3'-Diindolylmethane β-Hydroxybutyric acid (β-hydroxybutyrate) Abexinostat Acetoacetic acid
Acetoacetic acid
(acetoacetate) Allyl mercaptan Apicidin Belinostat Butyric acid
Butyric acid
(butyrate) Capsaicin Chidamide Citarinostat Curcumin Diallyl disulfide Entinostat Givinostat Indole-3-carbinol Kevetrin Martinostat Mocetinostat Nicotinamide Panobinostat Parthenolide Phenylbutyrate Pracinostat Quisinostat Resminostat Romidepsin Scriptaid Sodium butyrate Sodium oxybate
Sodium oxybate
(GHB sodium) Sodium phenylbutyrate Sodium valproate Sulforaphane Trapoxin B Trichostatin A Valnoctamide Valproic acid (valproate) Valproate
Valproate
pivoxil Valproate
Valproate
semisodium Valpromide Vorinostat
Vorinostat
(SAHA)

See also: Receptor/signaling modulators

v t e

Leukotriene
Leukotriene
signaling modulators

Receptor (ligands)

BLT

BLT1

Agonists: 12-HETE 20-Hydroxy-LTB4 Leukotriene
Leukotriene
B4 LY-255283

Antagonists: 20-Carboxy-LTB4 Amelubant CGS-23131 (LY-223982) CGS-25019C CP-105696 CP-195543 Etalocib LY-293111 Moxilubant ONO-4057 RG-14893 RP-69698 SB-209247 SC-53228 Ticolubant U-75302 ZK-158252

BLT2

Agonists: 12-HETE 12-HHT 12-HpETE 15-HETE 15-HpETE 20-Hydroxy-LTB4 Leukotriene
Leukotriene
B4

Antagonists: CP-195543 LY-255283 ZK-158252

CysLT

CysLT1

Agonists: Leukotriene
Leukotriene
C4 Leukotriene
Leukotriene
D4 Leukotriene
Leukotriene
E4

Antagonists: Ablukast BAYu9773 BAYu9916 BAYx7195 Cinalukast FPL-55712 ICI-198615 Iralukast LY-170680 Masilukast MK-571 Montelukast ONO-1078 Pobilukast Pranlukast Ritolukast SKF-104353 SR-2640 Sulukast Tipelukast Tomelukast Verlukast Zafirlukast ZD-3523

CysLT2

Agonists: Leukotriene
Leukotriene
C4 Leukotriene
Leukotriene
D4 Leukotriene
Leukotriene
E4

Antagonists: BAYu9773 BAYu9916

CysLTE

Agonists: Leukotriene
Leukotriene
E4

Enzyme (inhibitors)

5-LOX

2-TEDC Baicalein BW-A4C BW-B70C Caffeic acid CDC CJ-13610 Curcumin Fenleuton Hyperforin Hypericum perforatum
Hypericum perforatum
(St. John's Wort) Meclofenamic acid
Meclofenamic acid
(meclofenamate) Minocycline N-Stearoyldopamine Timegadine Zileuton

FLAP inhibitors: AM-103 AM-679 BAYx1005 MK-591 MK-886

12-LOX

2-TEDC 3-Methoxytropolone Baicalein CDC

15-LOX

2-TEDC CDC Luteolin PD-146176

LTA4H

Acebilustat Captopril DG-051 Fosinoprilat JNJ-26993135 SA-6541 SC-57461A Ubenimex
Ubenimex
(bestatin)

LTB4H

17-Octadecynoic acid

LTC4S

Azelastine MK-886

LTC4H

Acivicin Serine-borate complex

LTD4

Cilastatin Ubenimex
Ubenimex
(bestatin)

Others

Precursors: Linoleic acid γ-Linolenic acid (gamolenic acid) Dihomo-γ-linolenic acid Diacylglycerol Arachidonic acid 5-HPETE (arachidonic acid 5-hydroperoxide) Leukotriene
Leukotriene
A4

See also Receptor/signaling modulators Prostanoid
Prostanoid
signaling modulators Nuclear receptor modulators

v t e

Prostanoid
Prostanoid
signaling modulators

Receptor (ligands)

DP (D2)

DP1

Agonists: Prostaglandin D2 Treprostinil

Antagonists: Asapiprant Laropiprant Vidupiprant

DP2

Agonists: Indometacin Prostaglandin D2

Antagonists: ADC-3680 AZD-1981 Bay U3405 Fevipiprant MK-1029 MK-7246 QAV-680 Ramatroban Setipiprant Timapiprant TM30089 Vidupiprant

EP (E2)

EP1

Agonists: Beraprost Enprostil Iloprost
Iloprost
(ciloprost) Latanoprost Lubiprostone Misoprostol Prostaglandin E1
Prostaglandin E1
(alprostadil) Prostaglandin E2
Prostaglandin E2
(dinoprostone) Sulprostone

Antagonists: AH-6809 ONO-8130 SC-19220 SC-51089 SC-51322

EP2

Agonists: Butaprost Misoprostol Prostaglandin E1
Prostaglandin E1
(alprostadil) Prostaglandin E2
Prostaglandin E2
(dinoprostone) Treprostinil

Antagonists: AH-6809 PF-04418948 TG 4-155

EP3

Agonists: Beraprost Carbacyclin Cicaprost Enprostil Iloprost
Iloprost
(ciloprost) Isocarbacyclin Latanoprost Misoprostol Prostaglandin D2 Prostaglandin E1
Prostaglandin E1
(alprostadil) Prostaglandin E2
Prostaglandin E2
(dinoprostone) Remiprostol Sulprostone

Antagonists: L-798106

EP4

Agonists: Lubiprostone Misoprostol Prostaglandin E1
Prostaglandin E1
(alprostadil) Prostaglandin E2
Prostaglandin E2
(dinoprostone) TCS-2510

Antagonists: Grapiprant GW-627368 L-161982 ONO-AE3-208

Unsorted

Agonists: 16,16-Dimethyl Prostaglandin E2 Aganepag Carboprost Evatanepag Gemeprost Nocloprost Omidenepag Prostaglandin F2α
Prostaglandin F2α
(dinoprost) Simenepag Taprenepag

FP (F2α)

Agonists: Alfaprostol Bimatoprost Carboprost Cloprostenol Enprostil Fluprostenol Latanoprost Prostaglandin D2 Prostaglandin F2α
Prostaglandin F2α
(dinoprost) Sulotroban Tafluprost Travoprost Unoprostone

IP (I2)

Agonists: ACT-333679 AFP-07 Beraprost BMY-45778 Carbacyclin Cicaprost Iloprost
Iloprost
(ciloprost) Isocarbacyclin MRE-269 NS-304 Prostacyclin
Prostacyclin
(prostaglandin I2, epoprostenol) Prostaglandin E1
Prostaglandin E1
(alprostadil) Ralinepag Selexipag Taprostene TRA-418 Treprostinil

Antagonists: RO1138452

TP (TXA2)

Agonists: Carbocyclic thromboxane A2 I-BOP Thromboxane A2 U-46619 Vapiprost

Antagonists: 12-HETE 13-APA AA-2414 Argatroban Bay U3405 BMS-180,291 Daltroban Domitroban EP-045 GR-32191 ICI-185282 ICI-192605 Ifetroban Imitrodast L-655240 L-670596 Linotroban Mipitroban ONO-3708 ONO-11120 Picotamide Pinane thromboxane A2 Ramatroban Ridogrel S-145 Samixogrel Seratrodast SQ-28,668 SQ-29,548 Sulotroban Terbogrel Terutroban TRA-418

Unsorted

Arbaprostil Ataprost Ciprostene Clinprost Cobiprostone Delprostenate Deprostil Dimoxaprost Doxaprost Ecraprost Eganoprost Enisoprost Eptaloprost Esuberaprost Etiproston Fenprostalene Flunoprost Froxiprost Lanproston Limaprost Luprostiol Meteneprost Mexiprostil Naxaprostene Nileprost Nocloprost Ornoprostil Oxoprostol Penprostene Pimilprost Piriprost Posaraprost Prostalene Rioprostil Rivenprost Rosaprostol Spiriprostil Tiaprost Tilsuprost Tiprostanide Trimoprostil Viprostol

Enzyme (inhibitors)

COX (PTGS)

Salicylic acids: Aloxiprin Aspirin
Aspirin
(acetylsalicylic acid) Benorilate
Benorilate
(benorylate) Carbasalate calcium Diflusinal Dipyrocetyl Ethenzamide Guacetisal Magnesium salicylate Mesalazine
Mesalazine
(5-aminosalicylic acid) Methyl salicylate Salacetamide Salicin Salicylamide Salicylate
Salicylate
(salicylic acid) Salsalate Sodium salicylate Triflusal; Acetic acids: Aceclofenac Acemetacin Aclofenac Amfenac Alclofenac Bendazac Bromfenac Bufexamac Bumadizone Cinmetacin Clometacin Diclofenac Difenpiramide Etodolac Felbinac Fenclofenac Fentiazac Glucametacin Indometacin
Indometacin
(indomethacin) Indometacin
Indometacin
farnesil Ketorolac Lonazolac Mofezolac Nabumetone Oxametacin Oxindanac Proglumetacin Sulindac Sulindac
Sulindac
sulfide Tolmetin Zidometacin Zomepirac; Propionic acids: Alminoprofen Benoxaprofen Bucloxic acid (blucloxate) Butibufen Carprofen Dexibuprofen Dexindoprofen Dexketoprofen Fenbufen Fenoprofen Flunoxaprofen Flurbiprofen Ibuprofen Ibuproxam Indoprofen Ketoprofen Loxoprofen Miroprofen Naproxen Naproxcinod Oxaprozin Pirprofen Pranoprofen Suprofen Tarenflurbil Tepoxalin Tiaprofenic acid
Tiaprofenic acid
(tiaprofenate) Vedaprofen; Anthranilic acids (fenamic acids): Etofenamic acid (etofenamate) Floctafenic acid (floctafenate) Flufenamic acid
Flufenamic acid
(flufenamate) Meclofenamic acid
Meclofenamic acid
(meclofenamate) Mefenamic acid
Mefenamic acid
(mefenamate) Morniflumic acid (morniflumate) Niflumic acid
Niflumic acid
(niflumate) Talinflumic acid (talinflumate) Tolfenamic acid
Tolfenamic acid
(tolfenamate); Pyrazolones: Azapropazone Dipyrone Isopyrin Oxyphenbutazone Phenylbutazone; Enolic acids (oxicams): Ampiroxicam Droxicam Enolicam Isoxicam Lornoxicam Meloxicam Piroxicam Tenoxicam; 4-Aminoquinolines: Antrafenine Floctafenine Glafenine; Quinazolines: Fluproquazone Proquazone; Aminonicotinic acids: Clonixeril Clonixin Flunixin; Sulfonanilides: Flosulide Nimesulide; Aminophenols (anilines): Acetanilide AM-404 (N-arachidonoylaminophenol) Bucetin Paracetamol
Paracetamol
(acetaminophen) Parapropamol Phenacetin Propacetamol; Selective COX-2 inhibitors (coxibs): Apricoxib Celecoxib Cimicoxib Deracoxib Etoricoxib Firocoxib Lumiracoxib Mavacoxib Parecoxib Polmacoxib Robenacoxib Rofecoxib Tilmacoxib Valdecoxib; Others/unsorted: Anitrazafen Clobuzarit Curcumin DuP-697 FK-3311 Flumizole FR-122047 Glimepiride Hyperforin Itazigrel L-655240 L-670596 Licofelone Menatetrenone
Menatetrenone
(vitamin K2) NCX-466 NCX-4040 NS-398 Pamicogrel Resveratrol Romazarit Rosmarinic acid Rutecarpine Satigrel SC-236 SC-560 SC-58125 Tenidap Tiflamizole Timegadine Trifenagrel Tropesin

PGD2S

Retinoids Selenium
Selenium
(selenium tetrachloride, sodium selenite, selenium disulfide)

PGES

HQL-79

PGFS

Bimatoprost

PGI2S

Tranylcypromine

TXAS

Camonagrel Dazmegrel Dazoxiben Furegrelate Isbogrel Midazogrel Nafagrel Nicogrelate Ozagrel Picotamide Pirmagrel Ridogrel Rolafagrel Samixogrel Terbogrel U63557A

Others

Precursors: Linoleic acid γ-Linolenic acid (gamolenic acid) Dihomo-γ-linolenic acid Diacylglycerol Arachidonic acid Prostaglandin G2 Prostaglandin H2

See also Receptor/signaling modulators Leukotriene
Leukotriene
signaling modulators Nuclear receptor modulators

v t e

TRP channel modulators

TRPA

Activators

4-Hydroxynonenal 4-Oxo-2-nonenal 4,5-EET 12S-HpETE 15-Deoxy-Δ12,14-prostaglandin J2 α- Sanshool
Sanshool
(ginger, Sichuan and melegueta peppers) Acrolein Allicin
Allicin
(garlic) Allyl isothiocyanate
Allyl isothiocyanate
(mustard, radish, horseradish, wasabi) AM404 Bradykinin Cannabichromene
Cannabichromene
(cannabis) Cannabidiol
Cannabidiol
(cannabis) Cannabigerol
Cannabigerol
(cannabis) Cinnamaldehyde
Cinnamaldehyde
(cinnamon) CR gas
CR gas
(dibenzoxazepine; DBO) CS gas
CS gas
(2-chlorobenzal malononitrile) Curcumin
Curcumin
(turmeric) Dehydroligustilide (celery) Diallyl disulfide Dicentrine
Dicentrine
( Lindera
Lindera
spp.) Farnesyl thiosalicylic acid Formalin Gingerols (ginger) Hepoxilin A3 Hepoxilin B3 Hydrogen peroxide Icilin Isothiocyanate Ligustilide (celery, Angelica acutiloba) Linalool
Linalool
(Sichuan pepper, thyme) Methylglyoxal Methyl salicylate
Methyl salicylate
(wintergreen) N-Methylmaleimide Nicotine
Nicotine
(tobacco) Oleocanthal
Oleocanthal
(olive oil) Paclitaxel
Paclitaxel
(Pacific yew) Paracetamol
Paracetamol
(acetaminophen) PF-4840154 Phenacyl chloride Polygodial
Polygodial
(Dorrigo pepper) Shogaols (ginger, Sichuan and melegueta peppers) Tear gases Tetrahydrocannabinol
Tetrahydrocannabinol
(cannabis) Thiopropanal S-oxide
Thiopropanal S-oxide
(onion) Umbellulone
Umbellulone
(Umbellularia californica) WIN 55,212-2

Blockers

Dehydroligustilide (celery) Nicotine
Nicotine
(tobacco) Ruthenium red

TRPC

Activators

Adhyperforin
Adhyperforin
(St John's wort) Diacyl glycerol GSK1702934A Hyperforin
Hyperforin
(St John's wort) Substance P

Blockers

DCDPC DHEA-S Flufenamic acid GSK417651A GSK2293017A Meclofenamic acid N-(p-amylcinnamoyl)anthranilic acid Niflumic acid Pregnenolone sulfate Progesterone Pyr3 Tolfenamic acid

TRPM

Activators

ADP-ribose BCTC Calcium
Calcium
(intracellular) Cold Coolact P Cooling Agent 10 CPS-369 Eucalyptol
Eucalyptol
(eucalyptus) Frescolat MGA Frescolat ML Geraniol Hydroxycitronellal Icilin Linalool Menthol
Menthol
(mint) PMD 38 Pregnenolone sulfate Rutamarin (Ruta graveolens) Steviol glycosides (e.g., stevioside) (Stevia rebaudiana) Sweet tastants (e.g., glucose, fructose, sucrose; indirectly) Thio-BCTC WS-3 WS-12 WS-23

Blockers

Capsazepine Clotrimazole DCDPC Flufenamic acid Meclofenamic acid Mefenamic acid N-(p-amylcinnamoyl)anthranilic acid Nicotine
Nicotine
(tobacco) Niflumic acid Ruthenium red Rutamarin (Ruta graveolens) Tolfenamic acid TPPO

TRPML

Activators

MK6-83 PI(3,5)P2 SF-22

TRPP

Activators

Triptolide
Triptolide
(Tripterygium wilfordii)

Blockers

Ruthenium red

TRPV

Activators

2-APB 5',6'-EET 9-HODE 9-oxoODE 12S-HETE 12S-HpETE 13-HODE 13-oxoODE 20-HETE α- Sanshool
Sanshool
(ginger, Sichuan and melegueta peppers) Allicin
Allicin
(garlic) AM404 Anandamide Bisandrographolide (Andrographis paniculata) Camphor
Camphor
(camphor laurel, rosemary, camphorweed, African blue basil, camphor basil) Cannabidiol
Cannabidiol
(cannabis) Cannabidivarin
Cannabidivarin
(cannabis) Capsaicin
Capsaicin
(chili pepper) Carvacrol
Carvacrol
(oregano, thyme, pepperwort, wild bergamot, others) DHEA Diacyl glycerol Dihydrocapsaicin
Dihydrocapsaicin
(chili pepper) Estradiol Eugenol
Eugenol
(basil, clove) Evodiamine
Evodiamine
(Euodia ruticarpa) Gingerols (ginger) GSK1016790A Heat Hepoxilin A3 Hepoxilin B3 Homocapsaicin
Homocapsaicin
(chili pepper) Homodihydrocapsaicin
Homodihydrocapsaicin
(chili pepper) Incensole
Incensole
(incense) Lysophosphatidic acid Low pH (acidic conditions) Menthol
Menthol
(mint) N-Arachidonoyl dopamine N-Oleoyldopamine N-Oleoylethanolamide Nonivamide
Nonivamide
(PAVA) (PAVA spray) Nordihydrocapsaicin
Nordihydrocapsaicin
(chili pepper) Paclitaxel
Paclitaxel
(Pacific yew) Paracetamol
Paracetamol
(acetaminophen) Phorbol esters
Phorbol esters
(e.g., 4α-PDD) Piperine
Piperine
(black pepper, long pepper) Polygodial
Polygodial
(Dorrigo pepper) Probenecid Protons RhTx Rutamarin (Ruta graveolens) Resiniferatoxin
Resiniferatoxin
(RTX) (Euphorbia resinifera/pooissonii) Shogaols (ginger, Sichuan and melegueta peppers) Tetrahydrocannabivarin
Tetrahydrocannabivarin
(cannabis) Thymol
Thymol
(thyme, oregano) Tinyatoxin
Tinyatoxin
(Euphorbia resinifera/pooissonii) Tramadol Vanillin
Vanillin
(vanilla) Zucapsaicin

Blockers

α- Spinasterol
Spinasterol
( Vernonia
Vernonia
tweediana) AMG-517 Asivatrep BCTC Cannabigerol
Cannabigerol
(cannabis) Cannabigerolic acid (cannabis) Cannabigerovarin (cannabis) Cannabinol
Cannabinol
(cannabis) Capsazepine DCDPC DHEA DHEA-S Flufenamic acid GRC-6211 HC-067047 Lanthanum Meclofenamic acid N-(p-amylcinnamoyl)anthranilic acid NGD-8243 Niflumic acid Pregnenolone sulfate RN-1734 RN-9893 Ruthenium red SB-705498 Tivanisiran Tolfenamic acid

See also: Receptor/signaling modulators • Ion channe

.