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Hyperforin
Hyperforin
is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum
Hypericum
perforatum (St John's wort). Hyperforin
Hyperforin
(along with adhyperforin) is believed to be one of the three chief active constituents of St. John's wort
St. John's wort
-the other two being hypericin (along with pseudohypericin) and several flavonoid constituents.[1]

Contents

1 Occurrence 2 Chemistry 3 Pharmacokinetics 4 Biochemistry 5 See also 6 Further reading 7 References

Occurrence[edit] Hyperforin
Hyperforin
has only been found in significant amounts in Hypericum perforatum (St. John's wort) with other related species such as Hypericum
Hypericum
calycinum (Greater St. John's wort
St. John's wort
or Aaron's beard) containing lower levels of the phytochemical. It is thought to be a reuptake inhibitor.[2] It accumulates in oil glands, pistils, and fruits, probably as a plant defense against herbivory.[3] Other Hypericum
Hypericum
species contain low amounts of hyperforin.[4] Chemistry[edit] Hyperforin
Hyperforin
is a prenylated phloroglucinol derivative. The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry ( USSR Academy of Sciences
USSR Academy of Sciences
in Moscow) and published in 1975.[5][6] A total synthesis of the non-natural enantiomer of hyperforin was reported in 2010[7] and a total synthesis of the natural enantiomer was disclosed in 2012.[8] Hyperforin
Hyperforin
is unstable in the presence of light and oxygen.[9] Pharmacokinetics[edit] Some pharmacokinetic data on hyperforin is available for an extract containing 5% hyperforin. Maximal plasma levels (Cmax) in human volunteers were reached 3.5h after administration of an extract containing 14.8 mg hyperforin. Biological half-life (t1/2) and mean residence time were 9h and 12h respectively with an estimated steady state plasma concentration of 100 ng/mL (approx. 180 nM) for 3 doses/d. Linear plasma concentrations were observed within a normal dosage range and no accumulation occurred.[10] In healthy male volunteers, 612 mg dry extract of St. John's wort produced hyperforin pharmacokinetics characterised by a half life of 19.64 hours.[11] It appears to be metabolised, at least in part, by CYP3A and CYP2B into hydroxyl metabolites.[12] Biochemistry[edit]

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Hyperforin
Hyperforin
is believed to be the primary active constituent responsible for the antidepressant and anxiolytic properties of the extracts of St. John's wort.[13] It acts as a reuptake inhibitor of monoamines, including serotonin, norepinephrine, dopamine, and of GABA and glutamate, with IC50
IC50
values of 0.05-0.10 μg/mL for all compounds, with the exception of glutamate, which is in the 0.5 μg/mL range.[14] Hyperforin
Hyperforin
also inhibits the reuptake of glycine[15] and choline (IC50=8.5μM).[16] It also modulates acetylcholine release in rat hippocampus and facilitates acetylcholine release in the striatum.[17][18] It appears to exert these effects by activating the transient receptor potential ion channel TRPC6.[19] Activation of TRPC6
TRPC6
induces the entry of sodium and calcium into the cell which causes inhibition of monoamine reuptake.[19] It also antagonises the NMDA receptor, AMPA receptor
AMPA receptor
and GABA
GABA
receptors.[20][21] It inhibits TRPC6-degradation.[22] Its action on the TRPC6
TRPC6
cation channel is also believed to be responsible for its BDNF-like modulation of dendritic spine morphology in hippocampal pyramidal neurons.[23] Nootropic
Nootropic
effects of hyperforin have been observed in rats.[12] There is in vivo evidence that it can reduce biomarkers of Alzheimer's Disease in animal models and in vitro,[20][24] an action it seems to share with its analogue, tetrahydrohyperforin.[25][26][27] Hyperforin promotes mitochondrial function and the development of oligodendrocytes.[28] Hyperforin
Hyperforin
also induces cytochrome P450 enzymes CYP3A4
CYP3A4
and CYP2C9
CYP2C9
by binding to and activating the pregnane X receptor (PXR).[29] The induction of CYP3A caused by hypericum perforatum seems to be heavily dependent on its hyperforin content.[30] Hyperforin
Hyperforin
has been found to be a potent inhibitor of COX-1
COX-1
and 5-LO with IC50
IC50
values of 300nM and 90nM respectively, approximately 3-18 times stronger than aspirin.[31] Hyperforin
Hyperforin
is active against methicillin-resistant strains of Staphylococcus aureus
Staphylococcus aureus
(MRSA) with a minimal inhibitory concentration (MIC) value of 1.0 μg/mL (1.86μM),[32] as well as against other gram-positive bacteria.[33] Chemical analogues of hyperforin have also exhibited in vitro activity against various bacterial species.[34] Hyperforin
Hyperforin
also has the ability to kill Plasmodium falciparum
Plasmodium falciparum
in vitro .[35] Hyperforin
Hyperforin
also has anticancer effects in vitro and in vivo, which are likely the result of both its anti-angiogenic and pro-apoptotic effects,[36] and potentially anticlastogenic effect.[37] Several chemical analogues of hyperforin have also exhibited anticancer effects in vitro and in vivo.[38][39][40] Hyperforin
Hyperforin
also inhibits SIRT1 and SIRT2
SIRT2
with a IC50
IC50
of 15±0.5μM and 28±0.2μM respectively.[41]

Reuptake Inhibition

Neurotransmitter IC50
IC50
(nanomoles)

Norepinephrine 80 ± 24

Dopamine 102 ± 19

GABA 184 ± 41

5-HT 205 ± 45

Glutamate 829 ± 687

Choline 8500

Binding affinity
Binding affinity
(human receptors)

Receptor Ki (nanomoles)

DRD1 595.8[42]

Hyperforin
Hyperforin
and its semi-synthetic analogues

Hyperforin

Aristoforin

Hyperforin
Hyperforin
trimethoxybenzoate

Tetrahydrohyperforin

Octahydrohyperforin

Hyperforin
Hyperforin
nicotinate

See also[edit]

Adhyperforin Hypericin Hypericum Reuptake inhibitor Serotonin St John's Wort

Further reading[edit]

Beerhues L (October 2006). "Molecule of Interest: Hyperforin". Phytochemistry. 67 (20): 2201–7. doi:10.1016/j.phytochem.2006.08.017. PMID 16973193.  pubchem.ncbi.nlm.nih.gov

References[edit]

^ https://www.liebertpub.com/DContent/Files/SampleChapters/Sample_BotanicalMedicineFromBenchtoBeds.pdf ^ Roz N, Rehavi M (Jun 2003). " Hyperforin
Hyperforin
inhibits vesicular uptake of monoamines by dissipating pH gradient across synaptic vesicle membrane". Life Sciences. 73 (4): 461–70. doi:10.1016/s0024-3205(03)00295-9. PMID 12759140.  ^ Beerhues L (2006). "Hyperforin". Phytochemistry. 67 (20): 2201–7. doi:10.1016/j.phytochem.2006.08.017. PMID 16973193.  ^ Smelcerovic A, Spiteller M (March 2006). " Phytochemical
Phytochemical
analysis of nine Hypericum
Hypericum
L. species from Serbia and the F.Y.R. Macedonia". Die Pharmazie. 61 (3): 251–2. PMID 16599273.  ^ Bystrov NS; Gupta ShR; Dobrynin VN; Kolosov MN; Chernov BK (January 1976). "[Structure of the antibiotic hyperforin]". Doklady Akademii Nauk SSSR (in Russian). 226 (1): 88–90. PMID 1248360.  ^ Bystrov NS, Chernov BK, Dobrynin VN, Kolosov MN (1975). "[The structure of hyperforin]". Tetrahedron Letters. 16 (32): 2791–2794. doi:10.1016/S0040-4039(00)75241-5.  ^ Shimizu Y, Shi SL, Usuda H, Kanai M, Shibasaki M (February 2010). "Catalytic Asymmetric Total Synthesis of ent-Hyperforin". Angew Chem Int Ed. 49 (6): 1103–6. doi:10.1002/anie.200906678. PMID 20063336.  ^ Sparling B, Moebius D, Shair M (December 2012). "Enantioselective Total Synthesis of Hyperforin". J Am Chem Soc. 135 (2): 644–7. doi:10.1021/ja312150d. PMID 23270309.  ^ Liu, F; Pan, C; Drumm, P; Ang, CY (February 2005). "Liquid chromatography-mass spectrometry studies of St. John's wort
St. John's wort
methanol extraction: active constituents and their transformation". Journal of pharmaceutical and biomedical analysis. 37 (2): 303–12. doi:10.1016/j.jpba.2004.10.034. PMID 15708671.  ^ Biber, A; Fischer, H; Römer, A; Chatterjee, SS (June 1998). "Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers". Pharmacopsychiatry. 31 (Suppl 1): 36–43. doi:10.1055/s-2007-979344. PMID 9684946.  ^ Schulz, HU; Schürer, M; Bässler, D; Weiser, D (2005). "Investigation of the Bioavailability of Hypericin, Pseudohypericin, Hyperforin
Hyperforin
and the Flavonoids Quercetin and Isorhamnetin Following Single and Multiple Oral Dosing of a Hypericum
Hypericum
Extract Containing Tablet". Arzneimittelforschung. 55 (1): 15–22. doi:10.1055/s-0031-1296820. PMID 15727160.  ^ a b Zanoli, P (Fall 2004). "Role of hyperforin in the pharmacological activities of St. John's Wort" (PDF). CNS Drugs Reviews. 10 (3): 203–218. doi:10.1111/j.1527-3458.2004.tb00022.x. PMID 15492771.  ^ Newall, Carol A.; Joanne Barnes; Anderson, Linda R. (2002). Herbal medicines: a guide for healthcare professionals. London: Pharmaceutical Press. ISBN 0-85369-474-5.  ^ Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Müller WE (1998). " Hyperforin
Hyperforin
as a possible antidepressant component of hypericum extracts". Life Sci. 63 (6): 499–510. doi:10.1016/S0024-3205(98)00299-9. PMID 9718074.  ^ Marsh WL, Davies JA (October 2002). "The involvement of sodium and calcium ions in the release of amino acid neurotransmitters from mouse cortical slices elicited by hyperforin". Life Sciences. 71 (22): 2645–55. doi:10.1016/S0024-3205(02)02104-5. PMID 12354583.  ^ Buchholzer ML, Dvorak C, Chatterjee SS, Klein J (May 2002). "Dual modulation of striatal acetylcholine release by hyperforin, a constituent of St. John's wort". The Journal of Pharmacology and Experimental Therapeutics. 301 (2): 714–9. doi:10.1124/jpet.301.2.714. PMID 11961077.  ^ Buchholzer, ML; Dvorak, C; Chatterjee, SS; Klein, J (May 2002). "Dual modulation of striatal acetylcholine release by hyperforin, a constituent of St. John's wort" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 301 (2): 714–719. doi:10.1124/jpet.301.2.714. PMID 11961077.  ^ Kiewert, C; Buchholzer, ML; Hartmann, J; Chatterjee, SS; Klein, J (July 2004). "Stimulation of hippocampal acetylcholine release by hyperforin, a constituent of St. John's Wort". Neuroscience Letters. 364 (3): 195–198. doi:10.1016/j.neulet.2004.04.046. PMID 15196674.  ^ a b Leuner K, Kazanski V, Müller M, et al. (December 2007). "Hyperforin--a key constituent of St. John's wort
St. John's wort
specifically activates TRPC6
TRPC6
channels". The FASEB Journal. 21 (14): 4101–11. doi:10.1096/fj.07-8110com. PMID 17666455.  ^ a b Griffith, TN; Varela-Nallar, L; Dinamarca, MC; Inestrosa, NC (2010). "Neurobiological effects of Hyperforin
Hyperforin
and its potential in Alzheimer's disease therapy". Current Medicinal Chemistry. 17 (5): 391–406. doi:10.2174/092986710790226156. PMID 20015041.  ^ Medina, MA; Martínez-Poveda, B; Amores-Sánchez, MI; Quesada, AR (June 2006). "Hyperforin: More than an antidepressant bioactive compound?". Life Sciences. 79 (2): 105–111. doi:10.1016/j.lfs.2005.12.027. PMID 16438991.  ^ Lin, Y; Zhang, JC; Fu, J; Chen, F; Wang, J; Wu, ZL; Yuan, SY (February 2013). " Hyperforin
Hyperforin
attenuates brain damage induced by transient middle cerebral artery occlusion (MCAO) in rats via inhibition of TRPC6
TRPC6
channels degradation". Journal of Cerebral Blood Flow and Metabolism. 33 (2): 253–262. doi:10.1038/jcbfm.2012.164. PMC 3564196 . PMID 23149561.  ^ Leuner, K; Li, W; Amaral, MD; Rudolph, S; Calfa, G; Schuwald, AM; Harteneck, C; Inoue, T; Pozzo-Miller, L. " Hyperforin
Hyperforin
modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca(2+) -permeable TRPC6
TRPC6
channels". Hippocampus. 23 (1): 40–52. doi:10.1002/hipo.22052. PMC 3538039 . PMID 22815087.  ^ Dinamarca, MC; Cerpa, W; Garrido, J; Hancke, JL; Inestrosa, NC (November 2006). " Hyperforin
Hyperforin
prevents beta-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-beta-deposits" (PDF). Molecular Psychiatry. 11 (11): 1032–1048. doi:10.1038/sj.mp.4001866. PMID 16880827.  ^ Carvajal, FJ; Zolezzi, JM; Tapia-Rojas, C; Godoy, JA; Inestrosa, NC (January 2013). "Tetrahydrohyperforin decreases cholinergic markers associated with amyloid-β plaques, 4-hydroxynonenal formation, and caspase-3 activation in AβPP/PS1 mice". Journal of Alzheimer's Disease. 36 (1): 99–118. doi:10.3233/JAD-130230. PMID 23568104.  ^ Cerpa, W; Hancke, JL; Morazzoni, P; Bombardelli, E; Riva, A; Marin, PP; Inestrosa, NC (March 2010). "The hyperforin derivative IDN5706 occludes spatial memory impairments and neuropathological changes in a double transgenic Alzheimer's mouse model". Current Alzheimer Research. 7 (2): 126–133. doi:10.2174/156720510790691218. PMID 19939230.  ^ Carvajal, FJ; Inestrosa, NC (September 2011). "Interactions of AChE with Aβ Aggregates in Alzheimer's Brain: Therapeutic Relevance of IDN 5706" (PDF). Frontiers in Molecular Neuroscience. 4: 19. doi:10.3389/fnmol.2011.00019. PMC 3172730 . PMID 21949501.  ^ Wang, Y; Zhang, Y; He, J; Zhang, H; Xiao, L; Nazarali, A; Zhang, Z; Zhang, D; Tan, Q; Kong, J; Li, XM (November 2011). "Hyperforin promotes mitochondrial function and development of oligodendrocytes" (PDF). Journal of Neurochemistry. 119 (3): 555–568. doi:10.1111/j.1471-4159.2011.07433.x. PMID 21848657.  ^ Moore LB, Goodwin B, Jones SA, et al. (June 2000). "St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor". Proceedings of the National Academy of Sciences of the United States of America. 97 (13): 7500–2. doi:10.1073/pnas.130155097. PMC 16574 . PMID 10852961.  ^ Mueller, SC; Majcher-Peszynska, J; Mundkowski, RG; Uehleke, B; Klammt, S; Sievers, H; Lehnfeld, R; Frank, B; Thurow, K; Kundt, G; Drewelow, B (January 2009). "No clinically relevant CYP3A induction after St. John's wort
St. John's wort
with low hyperforin content in healthy volunteers" (PDF). European Journal of Clinical Pharmacology. 65 (1): 81–87. doi:10.1007/s00228-008-0554-y. PMID 18762932.  ^ Albert, D; Zündorf, I; Dingermann, T; Müller, WE; Steinhilber, D; Werz, O (December 2002). " Hyperforin
Hyperforin
is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase". Biochemical Pharmacology. 64 (12): 1767–1775. doi:10.1016/S0006-2952(02)01387-4. PMID 12445866.  ^ Reichling, J; Weseler, A; Saller, R (July 2001). "A current review of the antimicrobial activity of Hypericum
Hypericum
perforatum L". Pharmacopsychiatry. 34 Suppl 1: S116–8. doi:10.1055/s-2001-15514. PMID 11518059.  ^ Schempp, CM; Pelz, K; Wittmer, A; Schöpf, E; Simon, JC (June 1999). "Antibacterial activity of hyperforin from St John's wort, against multiresistant Staphylococcus aureus
Staphylococcus aureus
and gram-positive bacteria". Lancet. 353 (9170): 2129. doi:10.1016/S0140-6736(99)00214-7. PMID 10382704.  ^ Schiavone, BI; Rosato, A; Marilena, M; Gibbons, S; Bombardelli, E; Verotta, L; Franchini, C; Corbo, F (September 2013). "Biological Evaluation of Hyperforin
Hyperforin
and Its Hydrogenated Analogue on Bacterial Growth and Biofilm Production". J Nat Prod. 76 (9): 1819–1823. doi:10.1021/np400394c. PMID 23981190.  ^ Verotta, L; Appendino, G; Bombardelli, E; Brun, R (March 2007). "In vitro antimalarial activity of hyperforin, a prenylated acylphloroglucinol. A structure–activity study". Bioorganic & Medicinal Chemistry Letters. 17 (6): 1544–1548. doi:10.1016/j.bmcl.2006.12.100. PMID 17234416.  ^ Quiney, C; Billard, C; Salanoubat, C; Fourneron, JD; Kolb, JP (September 2006). "Hyperforin, a new lead compound against the progression of cancer and leukemia?" (PDF). Leukemia. 20 (9): 1519–1525. doi:10.1038/sj.leu.2404301. PMID 16791262.  ^ Imreova, P; Miadokova, C; Galova, E; Chankova, S; Chalupa, I. "POTENTIAL ANTICLASTOGENIC EFFECT OF HYPERFORIN" (PDF). Military Medical Science Letters. 82: 1–5. ISSN 0372-7025. Archived from the original (PDF) on 2014-02-21.  ^ Martínez-Poveda, B; Verotta, L; Bombardelli, E; Quesada, AR; Medina, MA (March 2010). "Tetrahydrohyperforin and Octahydrohyperforin Are Two New Potent Inhibitors of Angiogenesis" (PDF). PLoS ONE. 5 (3): e9558. doi:10.1371/journal.pone.0009558. PMC 2835552 . PMID 20224821.  ^ Sun, F; Liu, JY; He, F; Liu, Z; Wang, R; Wang, DM; Wang, YF; Yang, DP (August 2011). "In-vitro antitumor activity evaluation of hyperforin derivatives". Journal of Asian Natural Products Research. 13 (8): 688–699. doi:10.1080/10286020.2011.584532. PMID 21751836.  ^ Gartner, M; Müller, T; Simon, JC; Giannis, A; Sleeman, JP (January 2005). "Aristoforin, a novel stable derivative of hyperforin, is a potent anticancer agent". Chembiochem. 6 (1): 171–177. doi:10.1002/cbic.200400195. PMID 15593112.  ^ Gey, C; Kyrylenko, S; Hennig, L; Nguyen, LH; Büttner, A; Pham, HD; Giannis, A (July 2, 2007). " Phloroglucinol
Phloroglucinol
Derivatives Guttiferone G, Aristoforin, and Hyperforin: Inhibitors of Human Sirtuins SIRT1 and SIRT2". Angewandte Chemie International Edition. 46 (27): 5219–5222. doi:10.1002/anie.200605207. PMID 17516596.  ^ "Hyperforin". BindingDB. Retrieved 5 March 2015. 

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v t e

Antidepressants (N06A)

Specific reuptake inhibitors and/or receptor modulators

SSRIs

Citalopram Escitalopram Fluoxetine# Fluvoxamine Indalpine‡ Paroxetine Sertraline Zimelidine‡

SNRIs

Desvenlafaxine Duloxetine Levomilnacipran Milnacipran Tofenacin Venlafaxine

NRIs

Atomoxetine Reboxetine Viloxazine

NDRIs

Amineptine‡ Bupropion Nomifensine‡

NaSSAs

Mianserin Mirtazapine Setiptiline

SARIs

Etoperidone Nefazodone Trazodone

SMS

Vilazodone Vortioxetine

Others

Agomelatine Amisulpride Esketamine† Etryptamine‡ Indeloxazine flupentixol Ketamine† Medifoxamine‡ Metryptamine‡ Oxaflozane‡ Pivagabine‡ Tandospirone Teniloxazine Tianeptine

Tricyclic
Tricyclic
and tetracyclic antidepressants

TCAs

Amineptine‡ Amitriptyline# Amitriptylinoxide Butriptyline‡ Clomipramine# Demexiptiline‡ Desipramine Dibenzepin Dimetacrine‡ Dosulepin Doxepin Imipramine Imipraminoxide‡ Iprindole‡ Lofepramine Melitracen Metapramine‡ Nitroxazepine Nortriptyline Noxiptiline Opipramol Pipofezine Propizepine‡ Protriptyline Quinupramine‡ Tianeptine Trimipramine

TeCAs

Amoxapine Maprotiline Mianserin Mirtazapine Setiptiline

Others

Tiazesim

Monoamine
Monoamine
oxidase inhibitors

Non-selective

Irreversible: Benmoxin‡ Iproclozide‡ Iproniazid‡ Isocarboxazid Isoniazid# Linezolid# Mebanazine‡ Nialamide‡ Octamoxin‡ Phenelzine Pheniprazine‡ Phenoxypropazine‡ Pivhydrazine‡ Safrazine‡ Tedizolid Tranylcypromine

Reversible: Caroxazone‡

Mixed: Bifemelane

MAOA-selective

Reversible: Eprobemide Metralindole Minaprine‡ Moclobemide Pirlindole Tetrindole Toloxatone

MAOB-selective

Irreversible: Selegiline

Adjunctive therapies

Atypical antipsychotics (aripiprazole, brexpiprazole, lurasidone, olanzapine, quetiapine, risperidone) Buspirone Lithium (lithium carbonate, lithium citrate) Thyroid hormones (triiodothyronine (T3), levothyroxine (T4))

Miscellaneous

Ademetionine
Ademetionine
(SAMe) Hypericum
Hypericum
perforatum (St. John's Wort) Oxitriptan
Oxitriptan
(5-HTP) Rubidium chloride
Rubidium chloride
(RbCl) Tryptophan

#WHO-EM ‡Withdrawn from market Clinical trials:

†Phase III §Never to phase III

Pharmacodynamics

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
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
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
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
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
Pregnenolone
sulfate RN-1734 RN-9893 Ruthenium red SB-705498 Tivanisiran Tolfenamic acid

See also: Receptor/signaling modulators • Ion channel
Ion channel
modulators

v t e

Xenobiotic-sensing receptor modulators

CAR

Agonists: 6,7-Dimethylesculetin Amiodarone Artemisinin Benfuracarb Carbamazepine Carvedilol Chlorpromazine Chrysin CITCO Clotrimazole Cyclophosphamide Cypermethrin DHEA (prasterone) Efavirenz Ellagic acid Griseofulvin Methoxychlor Mifepristone Nefazodone Nevirapine Nicardipine Octicizer Permethrin Phenobarbital Phenytoin Pregnanedione (5β-dihydroprogesterone) Reserpine TCPOBOP Telmisartan Tolnaftate Troglitazone Valproic acid

Antagonists: 3,17β-Estradiol 3α-Androstanol 3α-Androstenol 3β-Androstanol 17-Androstanol AITC Ethinylestradiol Meclizine Nigramide J Okadaic acid PK-11195 S-07662 T-0901317

PXR

Agonists: 17α-Hydroxypregnenolone 17α-Hydroxyprogesterone Δ4-Androstenedione Δ5-Androstenediol Δ5-Androstenedione AA-861 Allopregnanediol Allopregnanedione (5α-dihydroprogesterone) Allopregnanolone
Allopregnanolone
(brexanolone) Alpha-Lipoic acid Ambrisentan AMI-193 Amlodipine besylate Antimycotics Artemisinin Aurothioglucose Bile acids Bithionol Bosentan Bumecaine Cafestol Cephaloridine Cephradine Chlorpromazine Ciglitazone Clindamycin Clofenvinfos Chloroxine Clotrimazole Colforsin Corticosterone Cyclophosphamide Cyproterone acetate Demecolcine Dexamethasone DHEA (prasterone) DHEA-S (prasterone sulfate) Dibunate sodium Diclazuril Dicloxacillin Dimercaprol Dinaline Docetaxel Docusate calcium Dodecylbenzenesulfonic acid Dronabinol Droxidopa Eburnamonine Ecopipam Enzacamene Epothilone B Erythromycin Famprofazone Febantel Felodipine Fenbendazole Fentanyl Flucloxacillin Fluorometholone Griseofulvin Guggulsterone Haloprogin Hetacillin potassium Hyperforin Hypericum
Hypericum
perforatum (St John's wort) Indinavir sulfate Lasalocid sodium Levothyroxine Linolenic acid LOE-908 Loratadine Lovastatin Meclizine Metacycline Methylprednisolone Metyrapone Mevastatin Mifepristone Nafcillin Nicardipine Nicotine Nifedipine Nilvadipine Nisoldipine Norelgestromin Omeprazole Orlistat Oxatomide Paclitaxel Phenobarbital Piperine Plicamycin Prednisolone Pregnanediol Pregnanedione (5β-dihydroprogesterone) Pregnanolone Pregnenolone Pregnenolone
Pregnenolone
16α-carbonitrile Proadifen Progesterone Quingestrone Reserpine Reverse triiodothyronine Rifampicin Rifaximin Rimexolone Riodipine Ritonavir Simvastatin Sirolimus Spironolactone Spiroxatrine SR-12813 Suberoylanilide Sulfisoxazole Suramin Tacrolimus Tenylidone Terconazole Testosterone isocaproate Tetracycline Thiamylal sodium Thiothixene Thonzonium bromide Tianeptine Troglitazone Troleandomycin Tropanyl 3,5-dimethulbenzoate Zafirlukast Zeranol

Antagonists: Ketoconazole Sesamin

See also Receptor/signaling modulators Nuclear recepto

.