Huperzine A

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Huperzine A
Huperzine A.png
HuperzineA3d.png
Clinical data
Other namesHupA
Routes of
administration 		By mouth
ATC code
Pharmacokinetic data
Elimination half-life 10–14 hours [1]
Identifiers
  • (1R,9R,13E)-1-Amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.02,7]trideca-2(7),3,10-trien-5-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.132.430 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H18N2O
Molar mass 242.322 g·mol−1
3D model (JSmol)
Melting point 217 to 219 °C (423 to 426 °F)
  • C/C=C/1\[C@@H]2CC3=C([C@]1(CC(=C2)C)N)C=CC(=O)N3
  • InChI=1S/C15H18N2O/c1-3-11-10-6-9(2)8-15(11,16)12-4-5-14(18)17-13(12)7-10/h3-6,10H,7-8,16H2,1-2H3,(H,17,18)/b11-3+/t10-,15+/m0/s1 Yes check.svgY
  • Key:ZRJBHWIHUMBLCN-YQEJDHNASA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)
Huperzine A capsules sold by the supplement company Life Extension, 200 mg per capsule Huperzine A Life Extension.jpg
Huperzine A capsules sold by the supplement company Life Extension, 200 μg per capsule
Huperzine A pills in China, 50 mg per tablet Huperzine A in China.jpg
Huperzine A pills in China, 50 μg per tablet

Huperzine A, a Lycopodium alkaloid, was first isolated in 1983 from Huperzia serrata , [2] [3] [4] a plant used in Chinese folk medicine. Huperzine A also exists in other Huperzia species, including H. elmeri, H. carinat, and H. aqualupian with varying quantities. [5]

Contents

Huperzine A has been investigated as a treatment for neurological conditions such as Alzheimer's disease, but a 2013 meta-analysis of those studies concluded that they were of poor methodological quality and the findings should be interpreted with caution. [6] [7]

Huperzine A inhibits acetylcholinesterase, the enzyme responsible for breaking down the neurotransmitter acetylcholine (ACh), and is also a weak NMDA receptor antagonist with poor affinity. It crosses the blood–brain barrier and is widely available as an over the counter nutritional supplement, marketed as a memory and concentration enhancer.

Adverse effects

Huperzine A may present with mild cholinergic side effects such as nausea, vomiting, and diarrhea. [7] Slight muscle twitching and slurred speech might also occur, as well as hypersalivation and sweating. The use of huperzine A during pregnancy and lactation is not recommended due to the lack of sufficient safety data. [8]

Pharmacology

Huperzine A is a potent, highly specific, reversible acetylcholinesterase inhibitor [9] [10] [11] [12] , with IC50 binding affinity of ~82 nM [13] . It is also a weak NMDA receptor antagonist [14] , with IC50 of ~65,000–82,000 nM [15] (65–82 µM); due to this relatively low affinity, huperzine A is unlikely to produce significant NMDA receptor blockade at clinically relevant concentrations in humans. Huperzine A readily crosses the blood–brain barrier and demonstrates central nervous system activity at therapeutic doses as low as 100 µg in humans. [16]

Acetylcholinesterase is an enzyme that catalyzes the breakdown of choline-based neurotransmitters, particularly acetylcholine (ACh), which plays a critical role in memory, learning, and behavior. The structure of the complex of huperzine A with acetylcholinesterase has been determined by X-ray crystallography (PDB code: 1VOT; see the 3D structure). [17]

Drug interactions

Huperzine A may have additive effects if taken with drugs causing bradycardia, such as beta-blockers, [18] which may decrease heart rate. Theoretically, there may be possible additive cholinergic effects if huperzine A is taken with other acetylcholinesterase inhibitors or cholinergic agents. [19]

Safety

Huperzine A, in spite of the possible cholinergic side effects, seems to have a wide margin of safety. Toxicology studies show huperzine A to be non-toxic even when administered at 50–100 times the human therapeutic dose. The extract is active for 6 hours at a dose of 2 μg/kg with no remarkable side effects. [20]

Synthesis

Two scalable and efficient total syntheses of huperzine A have been reported. [21] [22]

History

In 1989, a research study found [23]  that the chemical structure of the alkaloid selagine reported in 1960 from a study of Lycopodium slago L. [24] (analyzed using 60-MHz NMR) was identical to that of Huperzine A.

Research

Effects

Huperzine A has been investigated as a possible treatment for diseases characterized by neurodegeneration such as Alzheimer's disease, [25] [26] and there is some evidence from small-scale studies that it can benefit cognitive functioning, global clinical status, and ability to engage in activities of daily living (ADLs) among individuals with the disease. In a 2016 systematic review of systematic reviews, [27] huperzine A was associated with a standardized mean difference of 1.48 (95% CI, 0.95–2.02) compared to placebo on measures of ADL among people with dementia, but the evidence was very low-quality and uncertain. In a 2022 umbrella review, [28] huperzine A was associated with broad benefits to dementia patients' cognitive functioning, but the degree of heterogeneity in measurements and outcomes of the reviewed studies indicated publication bias toward huperzine A benefit.

Use in organophosphate poisoning

Huperzine A might be useful in the treatment of organophosphate nerve agent poisoning by preventing damage to the central nervous system caused by such agents. [29] [30]

References

  1. ↑ Li YX, Zhang RQ, Li CR, Jiang XH (2007). "Pharmacokinetics of huperzine A following oral administration to human volunteers". European Journal of Drug Metabolism and Pharmacokinetics. 32 (4): 183–187. doi:10.1007/BF03191002. PMID   18348466. S2CID   2702029.
  2. ↑ Liu JS, Zhu YL, Yu CM, Zhou YZ, Han YY, Wu FW, et al. (1986). "The structures of huperzine A and B, two new alkaloids exhibiting marked anticholinesterase activity". Canadian Journal of Chemistry. 64 (4): 837–839. Bibcode:1986CaJCh..64..837L. doi:10.1139/v86-137.
  3. ↑ US 5,177,082,Yu CM, Tang XC, Liu JS, Han YY,"Huperzines and analogs.",issued 5 January 1993
  4. ↑ Yu CM, Calhoun LA, Konder RM, Grant AS (2014). "Huperzimine, a novel Lycopodium alkaloid from Huperzia serrata". Canadian Journal of Chemistry. 92 (5): 406–410. Bibcode:2014CaJCh..92..406Y. doi:10.1139/cjc-2013-0520.
  5. ↑ Lim WH, Goodger JQ, Field AR, Holtum JA, Woodrow IE (September 2010). "Huperzine alkaloids from Australasian and southeast Asian Huperzia". Pharmaceutical Biology. 48 (9): 1073–1078. doi: 10.3109/13880209.2010.485619 . PMID   20731560.
  6. ↑ Yang G, Wang Y, Tian J, Liu JP (2013). "Huperzine A for Alzheimer's disease: a systematic review and meta-analysis of randomized clinical trials". PLOS ONE. 8 (9): e74916. Bibcode:2013PLoSO...874916Y. doi: 10.1371/journal.pone.0074916 . PMC   3781107 . PMID   24086396.{{cite journal}}: CS1 maint: article number as page number (link)
  7. 1 2 Li J, Wu HM, Zhou RL, Liu GJ, Dong BR (April 2008). Wu HM (ed.). "Huperzine A for Alzheimer's disease". The Cochrane Database of Systematic Reviews. CD005592 (2): CD005592. doi:10.1002/14651858.CD005592.pub2. PMID   18425924.{{cite journal}}: CS1 maint: article number as page number (link)
  8. ↑ "Huperzine A". Natural Standard: The Authority on Integrative Medicine. Natural Standard. Retrieved 29 October 2014.
  9. ↑ Wang R, Yan H, Tang XC (January 2006). "Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine". Acta Pharmacologica Sinica. 27 (1): 1–26. doi: 10.1111/j.1745-7254.2006.00255.x . PMID   16364207. Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase (AChE).
  10. ↑ Meletis CD, Barke JE (2004). Herbs and Nutrients for the Mind: A Guide to Natural Brain Enhancers. Greenwood Publishing Group. p. 191. ISBN   978-0-275-98394-9.
  11. ↑ Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ (April 2009). "Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis". Journal of Neural Transmission. 116 (4): 457–465. doi:10.1007/s00702-009-0189-x. PMID   19221692. S2CID   8655284.
  12. ↑ Tang XC, He XC, Bai DL (1999). "Huperzine A: A novel acetylcholinesterase inhibitor". Drugs of the Future. 24 (6): 647. doi:10.1358/dof.1999.024.06.545143.
  13. ↑ Herzon S, Tun MK (2012). "The pharmacology and therapeutic potential of (-)-huperzine A". Journal of Experimental Pharmacology. 4: 113–123. doi: 10.2147/JEP.S27084 . PMC   4863551 . PMID   27186124.
  14. ↑ Coleman BR, Ratcliffe RH, Oguntayo SA, Shi X, Doctor BP, Gordon RK, et al. (September 2008). "[+]-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats". Chemico-Biological Interactions. 175 (1–3): 387–395. Bibcode:2008CBI...175..387C. doi:10.1016/j.cbi.2008.05.023. PMID   18588864.
  15. ↑ Herzon S, Tun MK (2012). "The pharmacology and therapeutic potential of (-)-huperzine A". Journal of Experimental Pharmacology. 4: 113–123. doi: 10.2147/JEP.S27084 . PMC   4863551 . PMID   27186124.
  16. ↑ Patocka J (1998). "Huperzine A--an interesting anticholinesterase compound from the Chinese herbal medicine". Acta Medica. 41 (4): 155–157. doi: 10.14712/18059694.2019.181 . PMID   9951045.
  17. ↑ Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL (January 1997). "Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A". Nature Structural Biology. 4 (1): 57–63. doi:10.1038/nsb0197-57. PMID   8989325. S2CID   236518.
  18. ↑ Pepping J (March 2000). "Huperzine A". American Journal of Health-System Pharmacy. 57 (6): 530, 533–530, 534. doi: 10.1093/ajhp/57.6.530 . PMID   10754762.
  19. ↑ Skolnick AA (March 1997). "Old Chinese herbal medicine used for fever yields possible new Alzheimer disease therapy". JAMA. 277 (10): 776. doi:10.1001/jama.1997.03540340010004. PMID   9052690.[ failed verification ]
  20. ↑ Lallement G, Baille V, Baubichon D, Carpentier P, Collombet JM, Filliat P, et al. (May 2002). "Review of the value of huperzine as pretreatment of organophosphate poisoning". Neurotoxicology. 23 (1): 1–5. Bibcode:2002NeuTx..23....1L. doi:10.1016/S0161-813X(02)00015-3. PMID   12164543.
  21. ↑ un MK, Wüstmann DJ, Herzon SB (2011). "A robust and scalable synthesis of the potent neuroprotective agent (−)-huperzine A". Chemical Science. 2 (11): 2251–2253. doi:10.1039/C1SC00455G. S2CID   98224866.
  22. ↑ Tudhope SR, Bellamy JA, Ball A, Rajasekar D, Azadi-Ardakani M, Meera HS, et al. (2012). "Development of a Large-Scale Synthetic Route to Manufacture (−)-Huperzine A". Organic Process Research & Development. 16 (4): 635–642. doi:10.1021/op200360b.
  23. ↑ Ayer WA, Browne LM, Orszanska H, Valenta Z (October 1989). "Alkaloids of Lycopodium selago. On the identity of selagine with huperzine A and the structure of a related alkaloid". Canadian Journal of Chemistry. 67 (10): 1538–1540. Bibcode:1989CaJCh..67.1538A. doi:10.1139/v89-234.
  24. ↑ Valenta Z, Yoshimura H, Rogers EF, Ternbah M, Wiesner K (January 1960). "The structure of selagine". Tetrahedron Letters. 1 (31): 26–33. doi:10.1016/S0040-4039(01)99300-1.
  25. ↑ Zangara A (June 2003). "The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer's disease". Pharmacology, Biochemistry, and Behavior. 75 (3): 675–686. doi:10.1016/S0091-3057(03)00111-4. PMID   12895686. S2CID   36435892.
  26. ↑ Bai DL, Tang XC, He XC (March 2000). "Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease". Current Medicinal Chemistry. 7 (3): 355–374. doi:10.2174/0929867003375281. PMID   10637369.
  27. ↑ Laver K, Dyer S, Whitehead C, Clemson L, Crotty M (April 2016). "Interventions to delay functional decline in people with dementia: a systematic review of systematic reviews". BMJ Open. 6 (4): e010767. doi:10.1136/bmjopen-2015-010767. PMC   4854009 . PMID   27121704.{{cite journal}}: CS1 maint: article number as page number (link)
  28. ↑ Fan F, Liu H, Shi X, Ai Y, Liu Q, Cheng Y (2022-02-01). "The Efficacy and Safety of Alzheimer's Disease Therapies: An Updated Umbrella Review". Journal of Alzheimer's Disease. 85 (3): 1195–1204. doi:10.3233/JAD-215423. PMID   34924395. S2CID   245311001.
  29. ↑ Lallement G, Baille V, Baubichon D, Carpentier P, Collombet JM, Filliat P, et al. (May 2002). "Review of the value of huperzine as pretreatment of organophosphate poisoning". Neurotoxicology. 23 (1): 1–5. Bibcode:2002NeuTx..23....1L. doi:10.1016/s0161-813x(02)00015-3. PMID   12164543.
  30. ↑ Liu L, Sun JX (March 2005). "[Advances on study of organophosphate poisoning prevented by Huperzine A]". Wei Sheng Yan Jiu = Journal of Hygiene Research (in Chinese). 34 (2): 224–226. PMID   15952670.
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