Hyperforin

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Hyperforin
Hyperforin2DACS.svg
Hyperforin3Dan2.gif
Systematic (IUPAC) name
(1R,5S,6R,7S)-4-hydroxy-6-methyl-1,3,7-tris(3-methylbut-2-en-1-yl)-6-(4-methylpent-3-en-1-yl)-5-(2-methylpropanoyl)bicyclo[3.3.1]non-3-ene-2,9-dion
Clinical data
Legal status
  • US: OTC
  • Unscheduled
Dependence
liability		 Nil
Routes of
administration		 Oral
Pharmacokinetic data
Metabolism Hepatic and CYP3A & CYP2B
Biological half-life 9-19.64 hours
Identifiers
CAS Number 11079-53-1
ATC code none
PubChem CID: 114787
IUPHAR/BPS 2764
DrugBank DB01892 YesY
ChemSpider 16736597 YesY
UNII RM741E34FP YesY
KEGG C07608 YesY
ChEBI CHEBI:5834 YesY
Chemical data
Formula C35H52O4
Molecular mass 536.784973
  • CC(C)C(=O)[C@@]21C(=O)[C@@](C[C@H](C\C=C(/C)C)[C@@]1(C)CC\C=C(/C)C)(C\C=C(/C)C)C(=O)C(\C\C=C(/C)C)=C2\O
  • InChI=1S/C35H52O4/c1-22(2)13-12-19-33(11)27(16-14-23(3)4)21-34(20-18-25(7)8)30(37)28(17-15-24(5)6)31(38)35(33,32(34)39)29(36)26(9)10/h13-15,18,26-27,38H,12,16-17,19-21H2,1-11H3/t27-,33+,34+,35-/m0/s1 YesY
  • Key:IWBJJCOKGLUQIZ-HQKKAZOISA-N YesY
Physical data
Melting point 79–80 °C (174–176 °F)
Solubility in water 0.66 mg/mL (20 °C)
 NYesY (what is this?)  (verify)

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

Occurrence

Hyperforin has only been found in significant amounts in Hypericum perforatum (St. John's wort) with other related species such as Hypericum calycinum (Greater 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 species contain low amounts of hyperforin.[4]

Chemistry

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 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 is unstable in the presence of light and oxygen.[9]

Pharmacokinetics

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]

Biologic effects

Reuptake Inhibition
Neurotransmitter IC50 (nanomoles)
Norepinephrine 80 ± 24
Dopamine 102 ± 19
GABA 184 ± 41
5-HT 205 ± 45
Glutamate 829 ± 687
Choline 8500
Binding affinity (human receptors)
Receptor Ki (nanomoles)
DRD1 595.8[13]

Hyperforin is believed to be the primary active constituent responsible for the antidepressant and anxiolytic properties of the extracts of St. John's wort.[14] It acts as a reuptake inhibitor of monoamines, including serotonin, norepinephrine, dopamine, and of GABA and glutamate, with 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.[15] Hyperforin also inhibits the reuptake of glycine[16] and choline (IC50=8.5μM).[17] It also modulates acetylcholine release in rat hippocampus and facilitates acetylcholine release in the striatum.[18][19] It appears to exert these effects by activating the transient receptor potential ion channel TRPC6.[20] Activation of TRPC6 induces the entry of sodium and calcium into the cell which causes inhibition of monoamine reuptake.[20] It also antagonises the NMDA receptor, AMPA receptor and GABA receptors.[21][22]

Its action on TRPC6 may enable it to protect from ischaemic brain injury.[23] Its action on the TRPC6 cation channel is also believed to be responsible for its BDNF-like modulation of dendritic spine morphology in hippocampal pyramidal neurons.[24]

Hyperforin also induces cytochrome P450 enzymes CYP3A4 and CYP2C9 by binding to and activating the pregnane X receptor (PXR).[25] The induction of CYP3A caused by hypericum perforatum seems to be heavily dependent on its hyperforin content.[26]

Hyperforin has been found to be a potent inhibitor of COX-1 and 5-LO with IC50 values of 300nM and 90nM respectively, giving it an anti-inflammatory action of approximately 3-18 times stronger than aspirin (although it is taken in far lesser quantities).[27]

Hyperforin has topical antibiotic properties and is active against methicillin-resistant strains of Staphylococcus aureus (MRSA) with a minimal inhibitory concentration (MIC) value of 1.0 μg/mL (1.86μM),[28] as well as against other gram-positive bacteria.[29] Chemical analogues of hyperforin have also exhibited in vitro activity against various bacterial species.[30] Hyperforin also has in vitro antimalarial effects.[31]

Procognitive effects of hyperforin have been observed in rats.[12] In vivo evidence suggests its efficacy against Alzheimer's disease,[21][32] an action it seems to share with its analogue, tetrahydrohyperforin.[33][34][35]

Hyperforin also has anticancer effects, both in vitro and in vivo, which are likely the result of its both anti-angiogenic and pro-apoptotic effects.[36] Several chemical analogues of hyperforin have also exhibited anticancer effects in vitro and in vivo.[37][38][39] Hyperforin also has anticlastogenic effects.[40] Hyperforin also inhibits SIRT1 and SIRT2 with a IC50 of 15±0.5μM and 28±0.2μM respectively.[41]

In 2008 it was reported that men with premature ejaculation that were administered an immediate-release oral formulation reported lasting longer.[42] Hyperforin promotes mitochondrial function and the development of oligodendrocytes.[43]

Hyperforin and its semi-synthetic analogues
Hyperforin
Aristoforin
Hyperforin trimethoxybenzoate
Tetrahydrohyperforin
Octahydrohyperforin
Hyperforin nicotinate

See also

Further reading

References

  1. ↑ https://www.liebertpub.com/DContent/Files/SampleChapters/Sample_BotanicalMedicineFromBenchtoBeds.pdf
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Beerhues L. (2006). "Hyperforin." Phytochemistry 67 (20): 2201-7. PMID 16973193
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ 12.0 12.1 Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ 20.0 20.1 Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ 21.0 21.1 Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  24. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  25. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  26. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  27. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  28. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  29. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  30. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  31. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  32. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  33. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  34. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  35. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  36. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  37. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  38. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  39. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  40. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  41. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  42. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  43. ↑ Lua error in package.lua at line 80: module 'strict' not found.


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