Hyperforin: Difference between revisions

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== Chemistry ==
== Chemistry ==
Hyperforin is a [[Prenylation|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.<ref name="pmid1248360">{{cite journal |author1=Bystrov NS |author2=Gupta ShR |author3=Dobrynin VN |author4=Kolosov MN |author5=Chernov BK |title=[Structure of the antibiotic hyperforin] |language=Russian |journal=[[Doklady Akademii Nauk SSSR]] |volume=226 |issue=1 |pages=88–90 |date=January 1976 |pmid=1248360 |doi= |url=}}</ref><ref name="doi10.1016/S0040-4039(00)75241-5">{{cite journal |vauthors=Bystrov NS, Chernov BK, Dobrynin VN, Kolosov MN |title=[The structure of hyperforin] |language= |journal=Tetrahedron Letters |volume=16 |issue=32 |pages=2791–2794 |year=1975 |month= |pmid= |doi=10.1016/S0040-4039(00)75241-5 |url=}}</ref> A total synthesis of the non-natural enantiomer of hyperforin was reported in 2010<ref name="10.1002/anie.200906678">{{cite journal |vauthors=Shimizu Y, Shi SL, Usuda H, Kanai M, Shibasaki M |title=Catalytic Asymmetric Total Synthesis of ''ent''-Hyperforin |journal= Angew Chem Int Ed |volume=49 |issue=6 |pages=1103–6 |date=February 2010 | pmid= 20063336|doi=10.1002/anie.200906678| url=}}</ref> and a total synthesis of the natural enantiomer was disclosed in 2012.<ref name="10.1021/ja312150d">{{cite journal |vauthors=Sparling B, Moebius D, Shair M |title=Enantioselective Total Synthesis of Hyperforin |journal= J Am Chem Soc |volume=135|issue= 2|pages= 644–7|date=December 2012 | pmid=23270309 |doi=10.1021/ja312150d| url=}}</ref> <!--[[Total synthesis]] of hyperforin has not yet been accomplished, despite attempts by several research groups.<ref name="pmid15892032">{{cite journal |vauthors=Nicolaou KC, Carenzi GE, Jeso V |title=Construction of highly functionalized medium-sized rings: synthesis of hyperforin and perforatumone model systems |journal=Angewandte Chemie International Edition in English |volume=44 |issue=25 |pages=3895–9 |date=June 2005 |pmid=15892032 |doi=10.1002/anie.200500776 |url=}}</ref>-->
Hyperforin is a [[Prenylation|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.<ref name="pmid1248360">{{cite journal |author1=Bystrov NS |author2=Gupta ShR |author3=Dobrynin VN |author4=Kolosov MN |author5=Chernov BK |title=[Structure of the antibiotic hyperforin] |language=Russian |journal=[[Doklady Akademii Nauk SSSR]] |volume=226 |issue=1 |pages=88–90 |date=January 1976 |pmid=1248360 |doi= |url=}}</ref><ref name="doi10.1016/S0040-4039(00)75241-5">{{cite journal |vauthors=Bystrov NS, Chernov BK, Dobrynin VN, Kolosov MN |title=[The structure of hyperforin] |language= |journal=Tetrahedron Letters |volume=16 |issue=32 |pages=2791–2794 |year=1975 |month= |pmid= |doi=10.1016/S0040-4039(00)75241-5 |url=}}</ref> A total synthesis of the non-natural enantiomer of hyperforin was reported in 2010<ref name="10.1002/anie.200906678">{{cite journal |vauthors=Shimizu Y, Shi SL, Usuda H, Kanai M, Shibasaki M |title=Catalytic Asymmetric Total Synthesis of ''ent''-Hyperforin |journal= Angew Chem Int ed |volume=49 |issue=6 |pages=1103–6 |date=February 2010 | pmid= 20063336|doi=10.1002/anie.200906678| url=}}</ref> and a total synthesis of the natural enantiomer was disclosed in 2012.<ref name="10.1021/ja312150d">{{cite journal |vauthors=Sparling B, Moebius D, Shair M |title=Enantioselective Total Synthesis of Hyperforin |journal= J Am Chem Soc |volume=135|issue= 2|pages= 644–7|date=December 2012 | pmid=23270309 |doi=10.1021/ja312150d| url=http://nrs.harvard.edu/urn-3:HUL.InstRepos:12563735|format=Submitted manuscript }}</ref> <!--[[Total synthesis]] of hyperforin has not yet been accomplished, despite attempts by several research groups.<ref name="pmid15892032">{{cite journal |vauthors=Nicolaou KC, Carenzi GE, Jeso V |title=Construction of highly functionalized medium-sized rings: synthesis of hyperforin and perforatumone model systems |journal=Angewandte Chemie International Edition in English |volume=44 |issue=25 |pages=3895–9 |date=June 2005 |pmid=15892032 |doi=10.1002/anie.200500776 |url=}}</ref>-->


Hyperforin is unstable in the presence of light and [[oxygen]].<ref name="pmid15708671">{{cite journal |author1=Liu, F |author2=Pan, C |author3=Drumm, P |author4=Ang, CY |title=Liquid chromatography-mass spectrometry studies of St. John's wort methanol extraction: active constituents and their transformation |journal=Journal of pharmaceutical and biomedical analysis |volume=37 |issue=2 |pages=303–12 |date=February 2005 |pmid=15708671 |doi=10.1016/j.jpba.2004.10.034 |url=}}</ref>
Hyperforin is unstable in the presence of light and [[oxygen]].<ref name="pmid15708671">{{cite journal |author1=Liu, F |author2=Pan, C |author3=Drumm, P |author4=Ang, CY |title=Liquid chromatography-mass spectrometry studies of St. John's wort methanol extraction: active constituents and their transformation |journal=Journal of Pharmaceutical and Biomedical Analysis |volume=37 |issue=2 |pages=303–12 |date=February 2005 |pmid=15708671 |doi=10.1016/j.jpba.2004.10.034 |url=}}</ref>


== Pharmacokinetics ==
== Pharmacokinetics ==
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{{primary sources|section|date=February 2016}}
{{primary sources|section|date=February 2016}}


Hyperforin may be a constituent responsible for the [[antidepressant]] and [[anxiolytic]] properties of the extracts of [[St. John's wort]].<ref name="isbn0-85369-474-5">{{cite book |author1=Newall, Carol A. |author2=Joanne Barnes |author3=Anderson, Linda R. |title=Herbal medicines: a guide for healthcare professionals |publisher=Pharmaceutical Press |location=London |year=2002 |pages= |isbn=0-85369-474-5 |oclc= |doi=}}</ref> [[In vitro]], it acted as a [[reuptake inhibitor]] of [[monoamine]]s, including [[serotonin]], [[norepinephrine]], [[dopamine]], and of [[GABA]] and [[glutamate]], with [[IC50|IC<sub>50</sub>]] 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.<ref name="pmid9718074">{{cite journal |vauthors=Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Müller WE |title=Hyperforin as a possible antidepressant component of hypericum extracts |journal=Life Sci. |volume=63 |issue=6 |pages=499–510 |year=1998 |pmid=9718074 |doi=10.1016/S0024-3205(98)00299-9}}</ref> In other laboratory studies, hyperforin induced [[cytochrome P450]] [[enzyme]]s [[CYP3A4]] and [[CYP2C9]] by binding to and activating the [[PXR|pregnane X receptor]].<ref name="pmid10852961">{{cite journal |vauthors=Moore LB, Goodwin B, Jones SA, etal |title=St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=97 |issue=13 |pages=7500–2 |date=June 2000 |pmid=10852961 |pmc=16574 |doi=10.1073/pnas.130155097 |url=}}</ref>
Hyperforin may be a constituent responsible for the [[antidepressant]] and [[anxiolytic]] properties of the extracts of [[St. John's wort]].<ref name="isbn0-85369-474-5">{{cite book |author1=Newall, Carol A. |author2=Joanne Barnes |author3=Anderson, Linda R. |title=Herbal medicines: a guide for healthcare professionals |publisher=Pharmaceutical Press |location=London |year=2002 |pages= |isbn=978-0-85369-474-8 |oclc= |doi=}}</ref> [[In vitro]], it acted as a [[reuptake inhibitor]] of [[monoamine]]s, including [[serotonin]], [[norepinephrine]], [[dopamine]], and of [[GABA]] and [[glutamate]], with [[IC50|IC<sub>50</sub>]] 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.<ref name="pmid9718074">{{cite journal |vauthors=Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Müller WE |title=Hyperforin as a possible antidepressant component of hypericum extracts |journal=Life Sci. |volume=63 |issue=6 |pages=499–510 |year=1998 |pmid=9718074 |doi=10.1016/S0024-3205(98)00299-9}}</ref> In other laboratory studies, hyperforin induced [[cytochrome P450]] [[enzyme]]s [[CYP3A4]] and [[CYP2C9]] by binding to and activating the [[PXR|pregnane X receptor]].<ref name="pmid10852961">{{cite journal |vauthors=Moore LB, Goodwin B, Jones SA, etal |title=St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=97 |issue=13 |pages=7500–2 |date=June 2000 |pmid=10852961 |pmc=16574 |doi=10.1073/pnas.130155097 |url=}}</ref>


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==Research==
Two [[meta-analysis|meta-analyses]] of [[clinical trial]]s evaluating the efficacy of St. John's wort for treating mild-to-moderate [[depression (mood)|depression]] indicated a response similar to [[selective serotonin reuptake inhibitor]]s and with better tolerance, although the quality of the studies reviewed was limited by low numbers of subjects and short durations of treatment.<ref>{{cite journal|pmid=28064110|year=2017|last1=Ng|first1=Q. X|title=Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis|journal=Journal of Affective Disorders|volume=210|pages=211–221|last2=Venkatanarayanan|first2=N|last3=Ho|first3=C. Y|doi=10.1016/j.jad.2016.12.048}}</ref><ref>{{cite journal|pmc=4946846|year=2016|last1=Cui|first1=Y. H|title=A meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults|journal=Neuropsychiatric Disease and Treatment|volume=12|pages=1715–1723|last2=Zheng|first2=Y|pmid=27468236|doi=10.2147/NDT.S106752}}</ref>


== See also ==
== See also ==

Revision as of 17:02, 12 September 2018

Hyperforin
Clinical data
Dependence
liability		Nil
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • US: OTC
  • In general: unscheduled
Pharmacokinetic data
MetabolismHepatic and CYP3A & CYP2B
Elimination half-life9-19.64 hours
Identifiers
  • (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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.112.565 Edit this at Wikidata
Chemical and physical data
FormulaC35H52O4
Molar mass536.784973 g·mol−1
3D model (JSmol)
Melting point79–80 °C (174–176 °F)
Solubility in water0.66 mg/mL (20 °C)
  • 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 checkY
  • Key:IWBJJCOKGLUQIZ-HQKKAZOISA-N checkY
 ☒NcheckY (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 is attributed to provide the main antidepressant effect of St. John's wort, although there is little evidence that hyperforin and St. John's wort have any effect on depression.

Occurrence

Hyperforin has only been found in significant amounts in Hypericum perforatum with other related species such as Hypericum calycinum containing lower levels of the phytochemical. It accumulates in oil glands, pistils, and fruits, probably as a plant defensive compound.[1] Other Hypericum species contain low amounts of hyperforin.[2]

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.[3][4] A total synthesis of the non-natural enantiomer of hyperforin was reported in 2010[5] and a total synthesis of the natural enantiomer was disclosed in 2012.[6]

Hyperforin is unstable in the presence of light and oxygen.[7]

Pharmacokinetics

Some pharmacokinetic data on hyperforin is available for an extract containing 5% hyperforin. Maximal plasma levels (Cmax) in human volunteers were reached 3.5 hours after administration of an extract containing 14.8 mg hyperforin. Biological half-life (t1/2) and mean residence time were 9 hours and 12 hours, respectively, with an estimated steady state plasma concentration of 100 ng/mL (approx. 180 nM) for 3 doses per day. Linear plasma concentrations were observed within a normal dosage range and no accumulation occurred.[8]

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.[9]

Biochemistry

Hyperforin may be a constituent responsible for the antidepressant and anxiolytic properties of the extracts of St. John's wort.[10] In vitro, it acted 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.[11] In other laboratory studies, hyperforin induced cytochrome P450 enzymes CYP3A4 and CYP2C9 by binding to and activating the pregnane X receptor.[12]

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

Research

Two meta-analyses of clinical trials evaluating the efficacy of St. John's wort for treating mild-to-moderate depression indicated a response similar to selective serotonin reuptake inhibitors and with better tolerance, although the quality of the studies reviewed was limited by low numbers of subjects and short durations of treatment.[14][15]

See also

Further reading

  • Beerhues L (October 2006). "Molecule of Interest: Hyperforin". Phytochemistry. 67 (20): 2201–7. doi:10.1016/j.phytochem.2006.08.017. PMID 16973193.
  • Hyperforin, PubChem

References

  1. ^ Beerhues L (2006). "Hyperforin". Phytochemistry. 67 (20): 2201–7. doi:10.1016/j.phytochem.2006.08.017. PMID 16973193.
  2. ^ Smelcerovic A, Spiteller M (March 2006). "Phytochemical analysis of nine Hypericum L. species from Serbia and the F.Y.R. Macedonia". Die Pharmazie. 61 (3): 251–2. PMID 16599273.
  3. ^ 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.
  4. ^ 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. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  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.
  6. ^ Sparling B, Moebius D, Shair M (December 2012). "Enantioselective Total Synthesis of Hyperforin" (Submitted manuscript). J Am Chem Soc. 135 (2): 644–7. doi:10.1021/ja312150d. PMID 23270309.
  7. ^ Liu, F; Pan, C; Drumm, P; Ang, CY (February 2005). "Liquid chromatography-mass spectrometry studies of 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.
  8. ^ 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.
  9. ^ Schulz, HU; Schürer, M; Bässler, D; Weiser, D (2005). "Investigation of the Bioavailability of Hypericin, Pseudohypericin, Hyperforin and the Flavonoids Quercetin and Isorhamnetin Following Single and Multiple Oral Dosing of a Hypericum Extract Containing Tablet". Arzneimittelforschung. 55 (1): 15–22. doi:10.1055/s-0031-1296820. PMID 15727160.
  10. ^ Newall, Carol A.; Joanne Barnes; Anderson, Linda R. (2002). Herbal medicines: a guide for healthcare professionals. London: Pharmaceutical Press. ISBN 978-0-85369-474-8.
  11. ^ Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Müller WE (1998). "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.
  12. ^ 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.
  13. ^ "Hyperforin". BindingDB. Retrieved 5 March 2015.
  14. ^ Ng, Q. X; Venkatanarayanan, N; Ho, C. Y (2017). "Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis". Journal of Affective Disorders. 210: 211–221. doi:10.1016/j.jad.2016.12.048. PMID 28064110.
  15. ^ Cui, Y. H; Zheng, Y (2016). "A meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults". Neuropsychiatric Disease and Treatment. 12: 1715–1723. doi:10.2147/NDT.S106752. PMC 4946846. PMID 27468236.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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