Huperzine A

Huperzine A

Systematic (IUPAC) name
(1R,9S,13E)-1-Amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0^2,7]trideca-2(7),3,10-trien-5-one
Clinical data
Routes of administration	Oral
Pharmacokinetic data
Biological half-life	10-14h[1]
Identifiers
CAS Number	102518-79-6
ATC code	N06
DrugBank	DB01928
ChemSpider	16736021
UNII	0111871I23
ChEBI	CHEBI:78330
ChEMBL	CHEMBL395280
Synonyms	HupA
Chemical data
Formula	C15H18N2O
Molar mass	242.32 g/mol
SMILES C\C2=C\[C@H]\3CC=1NC(=O)\C=C/C=1[C@@](N)(C2)C/3=C\C
InChI 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 Key:ZRJBHWIHUMBLCN-YQEJDHNASA-N
Physical data
Melting point	217 to 219 °C (423 to 426 °F)
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Huperzine A is a naturally occurring sesquiterpene alkaloid compound found in the firmoss Huperzia serrata^[2] and in varying quantities in other Huperzia species, including H. elmeri, H. carinat, and H. aqualupian.^[3]

Huperzine A has been found, through multiple studies, to be effective as a medicine for helping people with neurological conditions such as Alzheimer's disease, but the meta-analysis of those studies concluded that they were poor quality and the findings should be interpreted with caution.^[4][5]

Pharmacological effects

Huperzine A is extracted from Huperzia serrata.^[2] It is a reversible acetylcholinesterase inhibitor^{[6] [7][8]} and NMDA receptor antagonist^[9] that crosses the blood-brain barrier.^[10] The structure of the complex of huperzine A with acetylcholinesterase has been determined by X-ray crystallography (PDB code: 1VOT; see the 3D structure).^[11]

For some years, huperzine A has been investigated as a possible treatment for diseases characterized by neurodegeneration – particularly Alzheimer's disease.^[2][12] A 2013 meta-analysis found that huperzine A may be efficacious in improving cognitive function, global clinical status, and activities of daily living for individuals with Alzheimer’s disease. However, due to the poor size and quality of the clinical trials reviewed, huperzine A should not be recommended as a treatment for Alzheimer’s disease until further high quality studies confirm its beneficial effects.^[4]

Huperzine A is also marketed as a dietary supplement with claims made for its ability to improve memory and mental function, ^[13] though these claims are not supported by high quality research.^[14] Huperzine A may also have a possible role in the treatment of myasthenia gravis.^[15]

Adverse effects

Huperzine A may present with mild cholinergic side effects such as nausea, vomiting and diarrhea.^[5]

The use of huperzine A during pregnancy and lactation is not recommended due to the lack of sufficient safety data.^[16]

Drug interactions

Huperzine A may have additive effects if taken with drugs causing bradycardia, such as beta-blockers.^[15] 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.^[17]

Synthesis

Two scalable and efficient total syntheses of huperzine A have been reported.^[18][19]

See also

• Acetylcholinesterase inhibitor and AChE inhibitors and substrates in Proteopedia

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.
2. Zangara A (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): 675–86. doi:10.1016/S0091-3057(03)00111-4. PMID 12895686.
3. Lim WH, Goodger JQ, Field AR, Holtum JA, Woodrow IE (2010). "Huperzine alkaloids from Australasian and southeast Asian Huperzia". Pharmaceutical biology 48 (9): 1073–8. doi:10.3109/13880209.2010.485619. PMID 20731560.
4. 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. doi:10.1371/journal.pone.0074916. PMC 3781107. PMID 24086396.
5. Li J, Wu HM, Zhou RL, Liu GJ, Dong BR (16 Apr 2008). "Huperzine A for Alzheimer’s disease". Cochrane Database Syst Rev (2): CD005592. doi:10.1002/14651858.CD005592.pub2. PMID 18425924.
6. Meletis, Chris D. and Jason E. Barke (2004). Herbs and Nutrients for the Mind: A Guide to Natural Brain Enhancers. Greenwood Publishing Group. p. 191. ISBN 0275983943.
7. Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ (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 (Vienna, Austria : 1996) 116 (4): 457–65. doi:10.1007/s00702-009-0189-x. PMID 19221692.
8. 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.
9. Coleman BR, Ratcliffe RH, Oguntayo SA, Shi X, Doctor BP, Gordon RK, Nambiar MP (2008). "+-Huperzine a treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats". Chemico-biological interactions 175 (1–3): 387–95. doi:10.1016/j.cbi.2008.05.023. PMID 18588864.
10. Patocka J (1998). "Huperzine A--an interesting anticholinesterase compound from the Chinese herbal medicine". Acta Medica (Hradec Kralove) 41 (4): 155–7. PMID 9951045.
11. Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL (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.
12. Bai DL, Tang XC, He XC (2000). "Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease". Current medicinal chemistry 7 (3): 355–74. doi:10.2174/0929867003375281. PMID 10637369.
13. Talbott, SM (2012). Huperzine A (HupA). A Guide to Understanding Dietary Supplements (Routledge). pp. 304–. ISBN 978-1-136-80570-7.
14. "Huperzine A: 3 Common Claims Unsupported By Science". Healthy but Smart. 2016-04-22. Retrieved 2016-05-03.
15. Pepping J (15 Mar 2000). "Huperzine A". Am J Health Syst Pharm 57 (6): 530, 533–4. PMID 10754762.
16. "Huperzine A". Natural Standard: The Authority on Integrative Medicine. Natural Standard. Retrieved 29 October 2014.
17. Skolnick AA (12 Mar 1997). "Old Chinese herbal medicine used for fever yields possible new Alzheimer Disease therapy". JAMA 277 (10): 776. doi:10.1001/jama.277.10.776. PMID 9052690.
18. Tun MK, Wüstmann DJ, Herzon SB (2011). "A robust and scalable synthesis of the potent neuroprotective agent (−)-huperzine A". Chemical Science 2 (11): 2251. doi:10.1039/C1SC00455G.
19. Tudhope SR, Bellamy JA, Ball A, Rajasekar D, Azadi-Ardakani M, Meera HS, Gnanadeepam JM, Saiganesh R, Gibson F, He L, Behrens CH, Underiner G, Marfurt J, Favre N (2012). "Development of a Large-Scale Synthetic Route to Manufacture (−)-Huperzine A". Organic Process Research & Development 16 (4): 635–642. doi:10.1021/op200360b.