Huperzine A: Difference between revisions

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			{{Short description\|Chemical compound}}
	{{chembox
			{{cs1 config\|name-list-style=vanc\|display-authors=6}}
	\| verifiedrevid = 451619690
			{{Drugbox
	\| Name = Huperzine A
			\| Verifiedfields = changed
	\| ImageFile = Huperzine A.png
			\| Watchedfields = changed
	\| ImageSize = 200px
			\| verifiedrevid = 461740300
	\| ImageName = Huperzine A
	\| ~~ImageFile1~~ = ~~HuperzineA3d~~.png		\| image = Huperzine A.png
	\| ~~ImageSize1~~ = ~~200px~~		\| width = 200
			\| image2 = HuperzineA3d.png
	\| ImageName1 = Huperzine A 3d
			\| width2 = 200
	\| IUPACName = (1''R'',9''S'',13''E'')- 1-Amino- 13-ethylidene- 11-methyl- 6-azatricyclo trideca- 2(7),3,10- trien- 5-one
			\| IUPAC_name = (1''R'',9''R'',13''E'')-1-Amino-13-ethylidene-11-methyl-6-azatricyclotrideca-2(7),3,10-trien-5-one
	\| OtherNames = HupA
			\| synonyms = HupA
	\| Section1 = {{Chembox Identifiers
			<!--Identifiers-->
			\| ATC_prefix = N06
			\| ATC_suffix =
	\| DrugBank_Ref = {{drugbankcite\|correct\|drugbank}}		\| DrugBank_Ref = {{drugbankcite\|correct\|drugbank}}
	\| DrugBank = DB01928		\| DrugBank = DB01928
			\| PubChem = 854026
	\| SMILES = C\C2=C\\3CC=1NC(=O)\C=C/C=1(N)(C2)C/3=C\C
	\| ChemSpiderID_Ref = {{chemspidercite\|correct\|chemspider}}		\| ChemSpiderID_Ref = {{chemspidercite\|correct\|chemspider}}
			\| ChEBI_Ref = {{ebicite\|changed\|EBI}}
			\| ChEBI = 78330
			\| ChEMBL_Ref = {{ebicite\|correct\|EBI}}
			\| ChEMBL = 395280
	\| ChemSpiderID = 16736021		\| ChemSpiderID = 16736021
			\| UNII_Ref = {{fdacite\|changed\|FDA}}
	\| InChI = 1/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
			\| UNII = 0111871I23
	\| InChIKey = ZRJBHWIHUMBLCN-YQEJDHNABN
			\| CAS_number_Ref = {{cascite\|changed\|??}}
			\| CAS_number = 102518-79-6
			<!--Clinical data-->
			\| tradename =
			\| Drugs.com =
			\| legal_AU =
			\| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
			\| legal_UK =
			\| legal_US =
			\| routes_of_administration = Oral
			<!--Pharmacokinetic data-->
			\| bioavailability =
			\| protein_bound =
			\| metabolism =
			\| elimination_half-life = 10-14h<ref>{{cite journal \| vauthors = Li YX, Zhang RQ, Li CR, Jiang XH \| title = Pharmacokinetics of huperzine A following oral administration to human volunteers \| journal = European Journal of Drug Metabolism and Pharmacokinetics \| volume = 32 \| issue = 4 \| pages = 183–187 \| date = 2007 \| pmid = 18348466 \| doi = 10.1007/BF03191002 \| s2cid = 2702029 }}</ref>
			\| excretion =
			<!--Physical data-->
			\| density =
			\| melting_point = 217
			\| melting_high = 219
			\| melting_notes =
			\| solubility =
			<!--Chemical data-->
			\| C=15 \| H=18 \| N=2 \| O=1
			\| smiles = C/C=C/1\2CC3=C(1(CC(=C2)C)N)C=CC(=O)N3
	\| StdInChI_Ref = {{stdinchicite\|correct\|chemspider}}		\| StdInChI_Ref = {{stdinchicite\|correct\|chemspider}}
	\| StdInChI = 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		\| StdInChI = 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
	\| StdInChIKey_Ref = {{stdinchicite\|correct\|chemspider}}		\| StdInChIKey_Ref = {{stdinchicite\|correct\|chemspider}}
	\| StdInChIKey = ZRJBHWIHUMBLCN-YQEJDHNASA-N		\| StdInChIKey = ZRJBHWIHUMBLCN-YQEJDHNASA-N
	\| CASNo_Ref = {{cascite\|correct\|??}}
	\| CASNo = 102518-79-6
	\| RTECS =
	}}
	\| Section2 = {{Chembox Properties
	\| Formula = C<sub>15</sub>H<sub>18</sub>N<sub>2</sub>O
	\| MolarMass = 242.32 g/mol
	\| Appearance =
	\| Density =
	\| Solubility =
	\| MeltingPt = 217–219 °C
	\| BoilingPt =
	\| pKb =
	}}
	<!--
	\| </nowiki><sub>D</sub>]]
	\| -147° (''c'' = 0.36, ])
	\|-
	-->
	\| Section7 = {{Chembox Hazards
	\| ExternalMSDS =
	\| MainHazards =
	\| FlashPt =
	\| RPhrases =
	\| SPhrases =
	}}
	\| Section8 = {{Chembox Related
	\| OtherCpds =
	}}
	}}		}}

			'''Huperzine A''' is a naturally-occurring ] ] compound found in the ] '']''<ref name="Zangara2003"/> and in varying quantities in other food ''Huperzia'' species, including ''H. elmeri'', ''H. carinat'', and ''H. aqualupian''.<ref>{{cite journal \| vauthors = Lim WH, Goodger JQ, Field AR, Holtum JA, Woodrow IE \| title = Huperzine alkaloids from Australasian and southeast Asian Huperzia \| journal = Pharmaceutical Biology \| volume = 48 \| issue = 9 \| pages = 1073–1078 \| date = September 2010 \| pmid = 20731560 \| doi = 10.3109/13880209.2010.485619 \| doi-access = free }}</ref> Huperzine A has been investigated as a treatment for neurological conditions such as ], but a 2013 ] of those studies concluded that they were of poor methodological quality and the findings should be interpreted with caution.<ref name="meta2013">{{cite journal \| vauthors = Yang G, Wang Y, Tian J, Liu JP \| title = Huperzine A for Alzheimer's disease: a systematic review and meta-analysis of randomized clinical trials \| journal = PLOS ONE \| volume = 8 \| issue = 9 \| pages = e74916 \| date = 2013 \| pmid = 24086396 \| pmc = 3781107 \| doi = 10.1371/journal.pone.0074916 \| doi-access = free \| bibcode = 2013PLoSO...874916Y }}</ref><ref name=cochranemeta /> Huperzine A inhibits the breakdown of the ] ] (ACh) by the enzyme ]. It is also an antagonist of the NMDA-receptor. It is commonly available over the counter as a ] and marketed as a memory and concentration ].
	'''Huperzine A''' is a naturally occurring sesquiterpene ] compound found in the plant ] '']''.<ref>{{cite journal\|author = Kozikowski, Alan P.; Tueckmantel, Werner\|title = Chemistry, Pharmacology, and Clinical Efficacy of the Chinese Nootropic Agent Huperzine A\|journal = Accounts of Chemical Research\|year = 1999\|volume = 32\|issue = 8\|pages = 641–650\|doi = 10.1021/ar9800892}}</ref>

			Huperzine A has also been noted to help induce ].<ref name="Ferris 2009">{{cite web\|title=Lucid Dreaming: A Beginner's Guide\|url=http://fourhourworkweek.com/2009/09/21/how-to-lucid-dream/\|website=The Four Hour Work Week\|accessdate=29 December 2016}}</ref>
	Huperzine A is also an ], which has a mechanism of action similar to ], ], and ]. A pro-drug form of Huperzine A (ZT-1) is under development as a treatment for Alzheimer's disease.<ref> Neurobiology of Aging Conference in New Orleans, Nov 2003.</ref>

	In the US, Huperzine A is sold as a dietary supplement for memory support. The botanical has been used in ] for centuries for the treatment of swelling, fever and blood disorders. Clinical trials in China have shown it to be effective in the treatment of Alzheimer's disease<ref name=china>{{cite journal\|doi=10.1007/s00702-009-0189-x\|title=Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis\|year=2009\|last1=Wang\|first1=Bai-Song\|last2=Wang\|first2=Hao\|last3=Wei\|first3=Zhao-hui\|last4=Song\|first4=Yan-yan\|last5=Zhang\|first5=Lu\|last6=Chen\|first6=Hong-Zhuan\|journal=Journal of Neural Transmission\|volume=116\|pages=457\|pmid=19221692\|issue=4}}</ref> and enhancing memory in students.<ref>{{cite journal\|pmid=10678121\|year=1999\|last1=Sun\|first1=QQ\|last2=Xu\|first2=SS\|last3=Pan\|first3=JL\|last4=Guo\|first4=HM\|last5=Cao\|first5=WQ\|title=Huperzine-A capsules enhance memory and learning performance in 34 pairs of matched adolescent students.\|volume=20\|issue=7\|pages=601–3\|journal=Zhongguo yao li xue bao = Acta pharmacologica Sinica}}</ref>

	==Pharmacological effects==		==Pharmacological effects==
			Huperzine A is extracted from '']''.<ref name="Zangara2003">{{cite journal \| vauthors = Zangara A \| title = The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer's disease \| journal = Pharmacology, Biochemistry, and Behavior \| volume = 75 \| issue = 3 \| pages = 675–686 \| date = June 2003 \| pmid = 12895686 \| doi = 10.1016/S0091-3057(03)00111-4 \| s2cid = 36435892 }}</ref> It is a reversible ]<ref>{{cite journal \| vauthors = Wang R, Yan H, Tang XC \| title = Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine \| journal = Acta Pharmacologica Sinica \| volume = 27 \| issue = 1 \| pages = 1–26 \| date = January 2006 \| pmid = 16364207 \| doi = 10.1111/j.1745-7254.2006.00255.x \| quote = Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase (AChE). \| doi-access = free }}</ref><ref>{{cite book \| url=https://books.google.com/books?id=a5AMBY9ekzcC&q=Huperzine&pg=PA191 \| title=Herbs and Nutrients for the Mind: A Guide to Natural Brain Enhancers \| publisher=Greenwood Publishing Group \| vauthors = Meletis CD, Barke JE \| date=2004 \| pages=191 \| isbn=978-0-275-98394-9}}</ref><ref name="Alzheimer 1996">{{cite journal \| vauthors = Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ \| title = Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis \| journal = Journal of Neural Transmission \| volume = 116 \| issue = 4 \| pages = 457–465 \| date = April 2009 \| pmid = 19221692 \| doi = 10.1007/s00702-009-0189-x \| s2cid = 8655284 }}</ref><ref>{{cite journal \| vauthors = Tang XC, He XC, Bai DL \| title=Huperzine A: A novel acetylcholinesterase inhibitor \| journal=Drugs of the Future \| date=1999 \| volume=24 \| issue=6 \| pages=647 \| doi=10.1358/dof.1999.024.06.545143 }}</ref> and ] antagonist<ref>{{cite journal \| vauthors = Coleman BR, Ratcliffe RH, Oguntayo SA, Shi X, Doctor BP, Gordon RK, Nambiar MP \| title = -Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats \| journal = Chemico-Biological Interactions \| volume = 175 \| issue = 1–3 \| pages = 387–395 \| date = September 2008 \| pmid = 18588864 \| doi = 10.1016/j.cbi.2008.05.023 }}</ref> that crosses the ].<ref>{{cite journal \| vauthors = Patocka J \| title = Huperzine A--an interesting anticholinesterase compound from the Chinese herbal medicine \| journal = Acta Medica \| volume = 41 \| issue = 4 \| pages = 155–157 \| date = 1998 \| pmid = 9951045 \| doi = 10.14712/18059694.2019.181 \| doi-access = free }}</ref> ] 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 ] (PDB code: ; ).<ref>{{cite journal \| vauthors = Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL \| title = Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A \| journal = Nature Structural Biology \| volume = 4 \| issue = 1 \| pages = 57–63 \| date = January 1997 \| pmid = 8989325 \| doi = 10.1038/nsb0197-57 \| s2cid = 236518 }}</ref>
	Huperzine A is an acetylcholinesterase inhibititor<ref name="Alzheimer 1996">{{cite journal\|pmid=19221692\|year=2009\|last1=Wang\|first1=BS\|last2=Wang\|first2=H\|last3=Wei\|first3=ZH\|last4=Song\|first4=YY\|last5=Zhang\|first5=L\|last6=Chen\|first6=HZ\|title=Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis.\|volume=116\|issue=4\|pages=457–65\|doi=10.1007/s00702-009-0189-x\|journal=Journal of neural transmission (Vienna, Austria : 1996)}}</ref> and ] antagonist,<ref>{{cite journal\|pmid=18588864\|year=2008\|last1=Coleman\|first1=BR\|last2=Ratcliffe\|first2=RH\|last3=Oguntayo\|first3=SA\|last4=Shi\|first4=X\|last5=Doctor\|first5=BP\|last6=Gordon\|first6=RK\|last7=Nambiar\|first7=MP\|title=+-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats.\|volume=175\|issue=1-3\|pages=387–95\|doi=10.1016/j.cbi.2008.05.023\|journal=Chemico-biological interactions}}</ref>.

			Huperzine A has been investigated as a possible treatment for diseases characterized by ] such as ],<ref name="Zangara2003" /><ref name="r1">{{cite journal \| vauthors = Bai DL, Tang XC, He XC \| title = Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease \| journal = Current Medicinal Chemistry \| volume = 7 \| issue = 3 \| pages = 355–374 \| date = March 2000 \| pmid = 10637369 \| doi = 10.2174/0929867003375281 }}</ref> and there is some evidence from small-scale studies that it can benefit cognitive functioning, global clinical status, and ability to engage in ] (ADLs) among individuals with the disease. In a 2016 ],<ref>{{cite journal \| vauthors = Laver K, Dyer S, Whitehead C, Clemson L, Crotty M \| title = Interventions to delay functional decline in people with dementia: a systematic review of systematic reviews \| journal = BMJ Open \| volume = 6 \| issue = 4 \| pages = e010767 \| date = April 2016 \| pmid = 27121704 \| pmc = 4854009 \| doi = 10.1136/bmjopen-2015-010767 }}</ref> huperzine A was associated with a ] of 1.48 (], 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,<ref>{{cite journal \| vauthors = Fan F, Liu H, Shi X, Ai Y, Liu Q, Cheng Y \| title = The Efficacy and Safety of Alzheimer's Disease Therapies: An Updated Umbrella Review \| journal = Journal of Alzheimer's Disease \| volume = 85 \| issue = 3 \| pages = 1195–1204 \| date = 2022-02-01 \| pmid = 34924395 \| doi = 10.3233/JAD-215423 \| s2cid = 245311001 }}</ref> huperzine A was associated with broad benefits to dementia patients' cognitive functioning, but the degree of ] in measurements and outcomes of the reviewed studies indicated ] toward huperzine A benefit.
	Huperzine A has also attracted the attention of US medical science. It is currently being investigated as a possible treatment for diseases characterized by neurodegeneration – particularly ].<ref>{{cite journal\|author = Zangara, A\|title = The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer's disease\|journal = Pharmacol Biochem Behav.\|year = 2003\|volume = 75\|issue = 3\|pages = 675–86\|doi = 10.1016/S0091-3057(03)00111-4\|pmid = 12895686}}</ref><ref name=r1>{{cite journal\|author = Bai, D. L.; Tang, X. C.; He, X. C.\|title = Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease\|pmid=10637369\|journal = Current Medicinal Chemistry\|year = 2000\|volume = 7 \|issue= 3\|pages = 355–374}}</ref> It has been found to be an ] of the enzyme ].<ref>{{cite journal\|author = Tang, X. C.; He, X. C.; Bai, D. L.\|title = Huperzine A: a novel acetylcholinesterase inhibitor\|journal = Drugs of the Future\|year = 1999\|volume = 24\|issue = 6\|pages = 647–663\|doi = 10.1358/dof.1999.024.06.545143}}</ref> The structure of the complex of huperzine A with acetylcholinesterase has been determined<ref>{{cite journal\|pmid= 8989325\|year=1997\|last1= Raves \|first1=ML\|last2=Harel\|first2=M\|last3=Pang\|first3=Y-P\|last4=Silman\|first4=I\|last5=Kozikowski\|first5=AP\|last6=Sussman\|first6=JL\|title=3D structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A.\|volume=4\|issue=1\|pages=57–63\|journal=Nature Struct Biol}}</ref>. by ] (PDB code: ; ).This is the same ] of pharmaceutical drugs such as ] and ] used to treat Alzheimer's disease. Huperzine A is also a ] ] which protects the brain against glutamate induced damage, and it appears to increase ] levels in rats.<ref>{{cite journal\|author = Tang, L., Wang, R., Tang, X.\|title = Effects of huperzine A on secretion of nerve growth factor in cultured rat cortical astrocytes and neurite outgrowth in rat PC12 cells\|journal = Acta Pharmacologica Sinica\|year = 2005\|volume = 26\|pages = 673–678\|doi = 10.1111/j.1745-7254.2005.00130.x\|pmid = 15916732\|issue = 6}}</ref>

			==Adverse effects==
	Clinical trials in China have shown that huperzine A is comparably effective to similar drugs on the market, and may even be a bit safer in terms of side effects.<ref name=china/> The ] has completed<ref name=r1/> a Phase II clinical trial<ref>, Alzherimer Research Forum</ref> to evaluate the safety and efficacy of huperzine A in the treatment of Alzheimer's disease in a ] of its effect on cognitive function.The study concluded that huperzine A 200 mug BID has no demonstrable cognitive effect in patients with mild to moderate AD.<ref>Rafii M.S., Walsh S., Little J.T., Behan K., Reynolds B., Ward C., Jin S., Thomas R., Aisen P.S.,"A phase II trial of huperzine A in mild to moderate Alzheimer disease". ''Neurology''. 76 (16) (pp 1389-1394), 2011.</ref>
			Huperzine A may present with mild ] side effects such as nausea, vomiting, and diarrhea.<ref name="cochranemeta">{{cite journal \| vauthors = Li J, Wu HM, Zhou RL, Liu GJ, Dong BR \| veditors = Wu HM \| title = Huperzine A for Alzheimer's disease \| journal = The Cochrane Database of Systematic Reviews \| volume = CD005592 \| issue = 2 \| pages = CD005592 \| date = April 2008 \| pmid = 18425924 \| doi = 10.1002/14651858.CD005592.pub2 }}</ref> Slight muscle twitching and slurred speech might also occur, as well as ] and sweating. The use of huperzine A during pregnancy and lactation is not recommended due to the lack of sufficient safety data.<ref name="Natural Standard">{{cite web\|title=Huperzine A\|url=https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=764#safety\|website=Natural Standard: The Authority on Integrative Medicine \|publisher=Natural Standard\|access-date=29 October 2014}}</ref>

			==Drug interactions==
	Possible side effects include breathing problems, tightness in the throat or chest, chest pain, skin hives, rash, itchy or swollen skin, upset stomach, ], vomiting, ] and ]. Most adverse events were cholinergic in nature and no serious adverse events occurred. Huperzine A is a well-tolerated drug.<ref name="Alzheimer 1996"/>
			Huperzine A may have ] if taken with drugs causing ], such as ]s,<ref name="pepping">{{cite journal \| vauthors = Pepping J \| title = Huperzine A \| journal = American Journal of Health-System Pharmacy \| volume = 57 \| issue = 6 \| pages = 530, 533-530, 534 \| date = March 2000 \| pmid = 10754762 \| doi = 10.1093/ajhp/57.6.530 \| doi-access = free }}</ref> which may decrease heart rate. Theoretically, there may be possible additive cholinergic effects if huperzine A is taken with other ]s or ] agents.<ref>{{cite journal \| vauthors = Skolnick AA \| title = Old Chinese herbal medicine used for fever yields possible new Alzheimer disease therapy \| journal = JAMA \| volume = 277 \| issue = 10 \| pages = 776 \| date = March 1997 \| pmid = 9052690 \| doi = 10.1001/jama.1997.03540340010004 }}</ref>

	==~~See also~~==		==Safety==
			Huperzine A, in spite of the possible cholinergic side effects, seems to have a wide margin of safety. ] 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.<ref name="Safety">{{cite journal \| vauthors = Lallement G, Baille V, Baubichon D, Carpentier P, Collombet JM, Filliat P, Foquin A, Four E, Masqueliez C, Testylier G, Tonduli L, Dorandeu F \| title = Review of the value of huperzine as pretreatment of organophosphate poisoning \| journal = Neurotoxicology \| volume = 23 \| issue = 1 \| pages = 1–5 \| date = May 2002 \| pmid = 12164543 \| doi = 10.1016/S0161-813X(02)00015-3 }}</ref>
	*] and in ]

			==Other possible uses==
	==References==
			Huperzine A might be useful in the treatment of ] by preventing damage to the ] caused by such agents.
	{{reflist\|2}}
			<ref name="Poisoning">{{cite web\|title=Review of the Value of Huperzine as Pretreatment of Organophosphate Poisoning\|url=https://nutritionreview.org/2013/04/huperzinea/\|website=Nutrition Review\|date=22 April 2013}}</ref>
			<ref name="Poisoning2">{{cite journal \| vauthors = Liu L, Sun JX \| title = \| journal = Wei Sheng Yan Jiu = Journal of Hygiene Research \| volume = 34 \| issue = 2 \| pages = 224–226 \| date = March 2005 \| pmid = 15952670 \| url = https://europepmc.org/article/med/15952670 }}</ref>

			==Synthesis==
	{{Cholinergics}}
			Two scalable and efficient ] of huperzine A have been reported.<ref>{{cite journal \| vauthors = un MK, Wüstmann DJ, Herzon SB \| title=A robust and scalable synthesis of the potent neuroprotective agent (−)-huperzine A \| journal=Chemical Science \| date=2011 \| volume=2 \| issue=11 \| pages=2251–2253 \| doi=10.1039/C1SC00455G \| s2cid=98224866 }}</ref><ref>{{cite journal \| vauthors = Tudhope SR, Bellamy JA, Ball A, Rajasekar D, Azadi-Ardakani M, Meera HS, Gnanadeepam JM, Saiganesh R, Gibson F, He L, Behrens CH \| title=Development of a Large-Scale Synthetic Route to Manufacture (−)-Huperzine A \| journal=Organic Process Research & Development \| date=2012 \| volume=16 \| issue=4 \| pages=635–642 \| doi=10.1021/op200360b }}</ref>

			== References ==
			{{Reflist\|2}}

			== External links ==
			* in ]

			{{Antidementia}}
			{{Acetylcholine metabolism and transport modulators}}
			{{Ionotropic glutamate receptor modulators}}

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Latest revision as of 00:31, 7 September 2024

Chemical compound

Pharmaceutical compound

Huperzine A
Clinical data


Other names	HupA
Routes of administration	Oral
ATC code	N06
Pharmacokinetic data
Elimination half-life	10-14h
Identifiers
IUPAC name (1R,9R,13E)-1-Amino-13-ethylidene-11-methyl-6-azatricyclotrideca-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
3D model (JSmol)	Interactive image
Melting point	217 to 219 °C (423 to 426 °F)
SMILES C/C=C/1\2CC3=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
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Huperzine A is a naturally-occurring sesquiterpene alkaloid compound found in the firmoss Huperzia serrata and in varying quantities in other food Huperzia species, including H. elmeri, H. carinat, and H. aqualupian. 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. 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.

Huperzine A has also been noted to help induce lucid dreaming.

Pharmacological effects

Huperzine A is extracted from Huperzia serrata. It is a reversible acetylcholinesterase inhibitor and NMDA receptor antagonist that crosses the blood–brain barrier. 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).

Huperzine A has been investigated as a possible treatment for diseases characterized by neurodegeneration such as Alzheimer's disease, 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, 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, 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.

Adverse effects

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

Drug interactions

Huperzine A may have additive effects if taken with drugs causing bradycardia, such as beta-blockers, 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.

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.

Other possible uses

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.

Synthesis

Two scalable and efficient total syntheses of huperzine A have been reported.

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.
^ 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.
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.
^ 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.
"Lucid Dreaming: A Beginner's Guide". The Four Hour Work Week. Retrieved 29 December 2016.
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. 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.
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.
"Huperzine A". Natural Standard: The Authority on Integrative Medicine. Natural Standard. Retrieved 29 October 2014.
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.
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. doi:10.1016/S0161-813X(02)00015-3. PMID 12164543.
"Review of the Value of Huperzine as Pretreatment of Organophosphate Poisoning". Nutrition Review. 22 April 2013.
Liu L, Sun JX (March 2005). "[Advances on study of organophosphate poisoning prevented by Huperzine A]". Wei Sheng Yan Jiu = Journal of Hygiene Research. 34 (2): 224–226. PMID 15952670.
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.

External links

AChE inhibitors and substrates in Proteopedia

v t e Psychoanaleptics: Anti-dementia agents (ATC code N06D and others)
AChE inhibitor medications	Benzgalantamine Donepezil (+memantine) Galantamine Ipidacrine Rivastigmine Tacrine
Other medications	Aducanumab Bifemelane Donanemab Ginkgo folium Lecanemab Meclofenoxate (centrophenoxine) Memantine (+donepezil) Nicergoline
Experimental BACE inhibitors	Lanabecestat Verubecestat

Acetylcholine metabolism and transport modulators

Enzyme
(modulators)

ChATTooltip Choline acetyltransferase

AChETooltip Acetylcholinesterase

Inhibitors: Reversible: Carbamates: Aldicarb
Aminocarb
Bendiocarb
Bufencarb
Carbaryl
Carbendazim
Carbetamide
Carbofuran
Carbosulfan
Chlorbufam
Chloropropham
Dimetilan
Ethienocarb
Ethiofencarb
Fenobucarb
Formetanate
Formparanate
Methiocarb
Methomyl
Metolcarb
Miotine
Oxamyl
Phenmedipham
Pinmicarb
Pirimicarb
Promecarb
Propamocarb
Propham
Propoxur
Thiodicarb
Thiofanox; Stigmines: Distigmine
Eptastigmine
Ganstigmine
Neostigmine +glycopyrronium bromide
Phenserine
Physostigmine
Pyridostigmine
Quilostigmine
Rivastigmine
Terestigmine; Others: Acotiamide
Ambenonium
Caffeine
Donepezil
EA-3990
EA-4056
Edrophonium
Galantamine
Huperzine A
Huprine W
Huprine X
Huprine Y
Ipidacrine
Itopride
Ladostigil
Minaprine
Octamethylene-bis(5-dimethylcarbamoxyisoquinolinium bromide)
T-1123
T-1152
T-1194
TL-599
TL-1238
Tacrine
Zanapezil

Irreversible: Organophosphates: 2-Ethoxycarbonyl-1-methylvinyl cyclohexyl methylphosphonate
Acephate
Armine
Azinphos-ethyl
Azinphos-methyl
BAY-29952
Bensulide
Cadusafos
Carbophenothion
Chlorethoxyfos
Chlorfenvinphos
Chlorpyrifos
Chlorpyrifos-methyl
Coumaphos
Crotylsarin
Cyanophos
Cyclosarin (GF)
Demephion
Demeton
Demeton-S-methyl
Dialifor
Diazinon
Dichlorvos
Dicrotophos
Dicyclohexyl phosphorofluoridate
Diisopropylphosphate
Diisopropyl fluorophosphate
Dimefox
Dimethoate
Dimethyl 4-(methylthio)phenyl phosphate
Dioxathion
Disulfoton
EA-2012
EA-2054
EA-2098
EA-2192
EA-2613
EA-3148
EA-4352
Echothiophate
Ethylsarin (GE)
Endothion
EPN
Ethion
Ethoprop
Fenamiphos
Fenitrothion
Fenthion
Fluorotabun
Fonofos
Formothion
Fosthiazate
GD-42
GH
GT-45
GV
Guanitoxin
Hexaethyl tetraphosphate (HETP)
Isofluorophate
Isoxathion
Leptophos
Malaoxon
Malathion
Mazidox
Methamidophos
Methidathion
Methyl phenkapton
Methylfluorophosphonylcholine (MFPCh)
Metrifonate
Mevinphos
Mipafox
Monocrotophos
MSPI
Naled
Novichok agent
Omethoate
Oxydemeton-methyl
Paraoxon
Parathion
Parathion-methyl
Phorate
Phosalone
Phosfolan
Phosmet
Phosphamidon
Phoxim
Pirimiphos-methyl
Profenofos
Prothoate
R-16661
Ro 3-0340
Ro 3-0346
Ro 3-0347
Ro 3-0351
Ro 3-0352
Ro 3-0397
Ro 3-0411
Ro 3-0412
Ro 3-0417
Ro 3-0419
Ro 3-0422
Ro 3-0433
Ronnel
Sarin (GB)
Schradan
Soman (GD)
Sulfotep (TEDP)
Tabun (GA)
Tebupirimfos
Temefos
Terbufos
Tetrachlorvinphos
Tetraethyl pyrophosphate (TEPP)
Triazofos
Tribufos
Trichlorfon
Trichloronate
Tricresyl phosphate
VE
VG
VM
VP
VS
VR
VX; Others: Demecarium
Fasciculins (green mamba toxins) (1, 2, 3, 4)
Onchidal (Onchidella binneyi)
Methanesulfonyl fluoride

BChETooltip Butyrylcholinesterase

Inhibitors: Affinine
Affinisine
Conodurine
Cymserine
Ladostigil
Profenamine (ethopropazine)
Rivastigmine
Tacrine
ZINC-12613047
Many of the other AChE inhibitors listed above

Transporter
(modulators)

CHTTooltip Choline transporter

Inhibitors: Hemicholinium-3 (hemicholine)
Triethylcholine

Enhancers: Coluracetam

VAChTTooltip Vesicular acetylcholine transporter

Inhibitors: Vesamicol

Release
(modulators)

Inhibitors

SNAP-25Tooltip Synaptosomal-associated protein 25 inactivators: Botulinum toxin (A, C, E)

VAMPTooltip Vesicle-associated membrane protein inactivators: Botulinum toxin (B, D, F, G)

Others: Bungarotoxins (β-bungarotoxin, γ-bungarotoxin)

Enhancers

LPHNTooltip Latrophilin agonists: α-Latrotoxin

Others: Atracotoxins (e.g., robustoxin, versutoxin)
Crotoxin

See also: Receptor/signaling modulators; Muscarinic acetylcholine receptor modulators; Nicotinic acetylcholine receptor modulators

v t e Ionotropic glutamate receptor modulators
AMPARTooltip α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor	Agonists: Main site agonists: 5-Fluorowillardiine Acromelic acid (acromelate) AMPA BOAA Domoic acid Glutamate Ibotenic acid Proline Quisqualic acid Willardiine; Positive allosteric modulators: Aniracetam Cyclothiazide CX-516 CX-546 CX-614 Farampator (CX-691, ORG-24448) CX-717 CX-1739 CX-1942 Diazoxide Hydrochlorothiazide (HCTZ) IDRA-21 LY-392098 LY-395153 LY-404187 LY-451646 LY-503430 Mibampator (LY-451395) Nooglutyl ORG-26576 Oxiracetam PEPA Pesampator (BIIB-104, PF-04958242) Piracetam Pramiracetam S-18986 Tulrampator (S-47445, CX-1632) Antagonists: ACEA-1011 ATPO Becampanel Caroverine CNQX Dasolampanel DNQX Fanapanel (MPQX) GAMS Kaitocephalin Kynurenic acid Kynurenine Licostinel (ACEA-1021) NBQX PNQX Selurampanel Tezampanel Theanine Topiramate YM90K Zonampanel; Negative allosteric modulators: Barbiturates (e.g., pentobarbital, sodium thiopental) Cyclopropane Enflurane Ethanol (alcohol) Evans blue GYKI-52466 GYKI-53655 Halothane Irampanel Isoflurane Perampanel Pregnenolone sulfate Sevoflurane Talampanel; Unknown/unsorted antagonists: Minocycline
KARTooltip Kainate receptor	Agonists: Main site agonists: 5-Bromowillardiine 5-Iodowillardiine Acromelic acid (acromelate) AMPA ATPA Domoic acid Glutamate Ibotenic acid Kainic acid LY-339434 Proline Quisqualic acid SYM-2081; Positive allosteric modulators: Cyclothiazide Diazoxide Enflurane Halothane Isoflurane Antagonists: ACEA-1011 CNQX Dasolampanel DNQX GAMS Kaitocephalin Kynurenic acid Licostinel (ACEA-1021) LY-382884 NBQX NS102 Selurampanel Tezampanel Theanine Topiramate UBP-302; Negative allosteric modulators: Barbiturates (e.g., pentobarbital, sodium thiopental) Enflurane Ethanol (alcohol) Evans blue NS-3763 Pregnenolone sulfate
NMDARTooltip N-Methyl-D-aspartate receptor	Agonists: Main site agonists: AMAA Aspartate Glutamate Homocysteic acid (L-HCA) Homoquinolinic acid Ibotenic acid NMDA Proline Quinolinic acid Tetrazolylglycine Theanine; Glycine site agonists: β-Fluoro-D-alanine ACBD ACC (ACPC) ACPD AK-51 Apimostinel (NRX-1074) B6B21 CCG D-Alanine D-Cycloserine D-Serine DHPG Dimethylglycine Glycine HA-966 L-687,414 L-Alanine L-Serine Milacemide Neboglamine (nebostinel) Rapastinel (GLYX-13) Sarcosine; Polyamine site agonists: Neomycin Spermidine Spermine; Other positive allosteric modulators: 24S-Hydroxycholesterol DHEATooltip Dehydroepiandrosterone (prasterone) DHEA sulfate (prasterone sulfate) Epipregnanolone sulfate Plazinemdor Pregnenolone sulfate SAGE-201 SAGE-301 SAGE-718 Antagonists: Competitive antagonists: AP5 (APV) AP7 CGP-37849 CGP-39551 CGP-39653 CGP-40116 CGS-19755 CPP Kaitocephalin LY-233053 LY-235959 LY-274614 MDL-100453 Midafotel (d-CPPene) NPC-12626 NPC-17742 PBPD PEAQX Perzinfotel PPDA SDZ-220581 Selfotel; Glycine site antagonists: 4-Cl-KYN (AV-101) 5,7-DCKA 7-CKA ACC ACEA-1011 ACEA-1328 Apimostinel (NRX-1074) AV-101 Carisoprodol CGP-39653 CNQX D-Cycloserine DNQX Felbamate Gavestinel GV-196771 Harkoseride Kynurenic acid Kynurenine L-689560 L-701324 Licostinel (ACEA-1021) LU-73068 MDL-105519 Meprobamate MRZ 2/576 PNQX Rapastinel (GLYX-13) ZD-9379; Polyamine site antagonists: Arcaine Co 101676 Diaminopropane Diethylenetriamine Huperzine A Putrescine; Uncompetitive pore blockers (mostly dizocilpine site): 2-MDP 3-HO-PCP 3-MeO-PCE 3-MeO-PCMo 3-MeO-PCP 4-MeO-PCP 8A-PDHQ 18-MC α-Endopsychosin Alaproclate Alazocine (SKF-10047) Amantadine Aptiganel Argiotoxin-636 Arketamine ARL-12495 ARL-15896-AR ARL-16247 Budipine Coronaridine Delucemine (NPS-1506) Dexoxadrol Dextrallorphan Dextromethadone Dextromethorphan Dextrorphan Dieticyclidine Diphenidine Dizocilpine Ephenidine Esketamine Etoxadrol Eticyclidine Fluorolintane Gacyclidine Ibogaine Ibogamine Indantadol Ketamine Ketobemidone Lanicemine Levomethadone Levomethorphan Levomilnacipran Levorphanol Loperamide Memantine Methadone Methorphan Methoxetamine Methoxphenidine Milnacipran Morphanol NEFA Neramexane Nitromemantine Noribogaine Norketamine Orphenadrine PCPr PD-137889 Pethidine (meperidine) Phencyclamine Phencyclidine Propoxyphene Remacemide Rhynchophylline Rimantadine Rolicyclidine Sabeluzole Tabernanthine Tenocyclidine Tiletamine Tramadol; Ifenprodil (NR2B) site antagonists: Besonprodil Buphenine (nylidrin) CO-101244 (PD-174494) Eliprodil Haloperidol Isoxsuprine Radiprodil (RGH-896) Rislenemdaz (CERC-301, MK-0657) Ro 8-4304 Ro 25-6981 Safaprodil Traxoprodil (CP-101606); NR2A-selective antagonists: MPX-004 MPX-007 TCN-201 TCN-213; Cations: Hydrogen Magnesium Zinc; Alcohols/volatile anesthetics/related: Benzene Butane Chloroform Cyclopropane Desflurane Diethyl ether Enflurane Ethanol (alcohol) Halothane Hexanol Isoflurane Methoxyflurane Nitrous oxide Octanol Sevoflurane Toluene Trichloroethane Trichloroethanol Trichloroethylene Urethane Xenon Xylene; Unknown/unsorted antagonists: ARR-15896 Bumetanide Caroverine Conantokin D-αAA Dexanabinol Flufenamic acid Flupirtine FPL-12495 FR-115427 Furosemide Hodgkinsine Ipenoxazone (MLV-6976) MDL-27266 Metaphit Minocycline MPEP Niflumic acid Pentamidine Pentamidine isethionate Piretanide Psychotridine Transcrocetin (saffron) Unsorted: Allosteric modulators: AGN-241751
See also: Receptor/signaling modulators Metabotropic glutamate receptor modulators Glutamate metabolism/transport modulators

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