Huperzine A

Huperzine A
Clinical data
Other names	HupA
Routes of; administration	By mouth
ATC code	N06 ;
Pharmacokinetic data
Elimination half-life	10–14 hours
Identifiers
	IUPAC name (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	102518-79-6 ;
PubChem CID	854026;
DrugBank	DB01928 ;
ChemSpider	16736021 ;
UNII	0111871I23;
ChEBI	CHEBI:78330 ;
ChEMBL	ChEMBL395280 ;
CompTox Dashboard (EPA)	DTXSID8046038 ;
ECHA InfoCard	100.132.430
Chemical and physical data
Formula	C15H18N2O
Molar mass	242.322 g·mol−1
3D model (JSmol)	Interactive image;
Melting point	217 to 219 °C (423 to 426 °F)
	SMILES C/C=C/1\[C@@H]2CC3=C([C@]1(CC(=C2)C)N)C=CC(=O)N3;
	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 ;
	(what is this?) (verify)

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]

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 the breakdown of the neurotransmitter acetylcholine (ACh) by the enzyme acetylcholinesterase. It is also an antagonist of the NMDA receptor. It is commonly available over the counter as a nutritional supplement and 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 reversible acetylcholinesterase inhibitor^[9]^[10]^[11]^[12] and NMDA receptor antagonist^[13] that crosses the blood–brain barrier.^[14] Acetylcholinesterase is an enzyme that catalyzes the breakdown of the neurotransmitter ACh and other choline esters that function as neurotransmitters. The structure of the complex of huperzine A with acetylcholinesterase has been determined by X-ray crystallography (PDB code: 1VOT; see the 3D structure).^[15]

Drug interactions

Huperzine A may have additive effects if taken with drugs causing bradycardia, such as beta-blockers,^[16] 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]

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.^[18]

Synthesis

Two scalable and efficient total syntheses of huperzine A have been reported.^[19]^[20]

History

In 1989, a research study found^[21] that the chemical structure of the alkaloid selagine reported in 1960 from a study of Lycopodium slago L.^[22] (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,^[23]^[24] 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,^[25] 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,^[26] 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.^[27]^[28]

References

^ 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.
^ 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.
^ US 5,177,082, Yu CM, Tang XC, Liu JS, Han YY, "Huperzines and analogs.", issued 5 January 1993
^ 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.
^ 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.
^ 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.
^ ^a ^b 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.
^ "Huperzine A". Natural Standard: The Authority on Integrative Medicine. Natural Standard. Retrieved 29 October 2014.
^ 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).
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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]}
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.