Description
Huperzine A is obtained from Huperzia serrata, which is the perennial fern. It
shows activities in antipyretic, hemostasis, and dehumidification and is used for the
treatment in folk of pneumonia, lung abscess, hematemesis, hematochezia, traumatic injury, etc.
Chemical Properties
Pale Brown Solid
Physical properties
Appearance: white crystalline powder. Bitter with hygroscopicity. Solubility: easily
soluble in chloroform, soluble in methanol and ethanol, and slightly soluble in
water. Melting point: 211–216?°C.
History
In the 1980s, Chinese scholars isolated huperzine A from Lycopodiales,
Huperziaceae, Phlegmariurus fordii, and Huperzia serrata (Thunb.) Trevis.
At present, about 120 chemical components have been isolated and identified from
the plant, including 90 lycopodium alkaloids and 32 lycopodium triterpenes.
Huperzine A has the most potent inhibition on acetylcholinesterase activity, followed by huperzine B and 6β-hydroxy huperzine A.?These three compounds belong
to lycodine-type lycopodium alkaloids. The full synthesis of
huperzine A is complex and costly. Therefore, it is a focus to develop biotransformation or semisynthesis with other alkaloids as lead compounds on the basis of the
intrinsic relationship among different kinds of alkaloids
After the determination of chemical structure of huperzine A in 1986, it was
found to be the same alkaloid as selagine separated from Lycopodium selago by
Valenta in the 1960s, so it was classified as lycodine-type alkaloid. Huperzine A is
a potent reversible inhibitor of AChE, and its ability to improve learning and memory has been validated in animal models. It was approved for treatment in Alzheimer’s
disease (AD) in China in 1996
Due to the high cost of extraction of huperzine A, research on its chemical synthesis has been the focus at home and abroad since 1986. It has been found that the
chiral structure of huperzine A is essential for its biological activity; the inhibitory
activity on AChE of natural products (-)?- huperzine A is twice as its raceme and
38–50 times as its enantiomer (+)?- huperzine A which is not a natural product, so
the chemical synthesis of natural product (-)?- huperzine A has received extensive
attention. The chemical preparation method of (-)?- huperzine A can be divided into
asymmetric synthesis and raceme separation and is limited to a small amount preparation in laboratory for the high cost.
Considering the difficulty of realizing unique bridge ring and amino structure of
(-)?- huperzine A and achieving its full synthesis and structural modification, scientists are trying to synthesize analogues of huperzine A with simple structure and
AchE inhibitory activity. It was found that the activity of spearmint huperzine A was
similar to that of huperzine A, with improved selectivity and poor chemical stability.
It was modified structurally to obtain ZT-1 .
Definition
ChEBI: Huperzine A is a sesquiterpene alkaloid isolated from a club moss Huperzia serrata that has been shown to exhibit neuroprotective activity. It is also an effective inhibitor of acetylcholinesterase and has attracted interest as a therapeutic candidate for Alzheimer's disease. It has a role as an EC 3.1.1.7 (acetylcholinesterase) inhibitor, a neuroprotective agent, a plant metabolite and a nootropic agent. It is a sesquiterpene alkaloid, a pyridone, a primary amino compound and an organic heterotricyclic compound. It is a conjugate base of a huperzine A(1+).
Preparation
(-)-Huperzine A, a Lyco-podium alkaloid isolated in 1986 from the club moss Huperzia serrata, has drawn considerable attention after it was revealed to be a potent, selective, and reversible AChE inhibitor.
The total synthesis of Lycopodium alkaloid (-)-huperzine A has been accomplished in 10 steps with 17% overall yield from commercially abundant (R)-pulegone. The synthetic route features an efficient synthesis of 4 via a Buchwald–Hartwig coupling reaction, a dianion-mediated highly stereoselective alkylation of 4, and a rare example of an intramolecular Heck reaction of an enamine-type substrate. The stereoselective β-elimination and the accompanying Wagner–Meerwein rearrangement are of particular interest.
[1] RUI DING Guo Q L Bing Feng Sun*. An Efficient Total Synthesis of (-)-Huperzine A [J]. Organic Letters, 2012, 14 17: 4446-4449. DOI:
10.1021/ol301951r.
[2] RUI DING. Divergent Total Synthesis of the Lycopodium Alkaloids Huperzine A, Huperzine B, and Huperzine U[J]. The Journal of Organic Chemistry, 2013, 79 1: 240-250. DOI:
10.1021/jo402419h.
[3] TUN M K M, WüSTMANN D J, HERZON S B. A robust and scalable synthesis of the potent neuroprotective agent (-)-huperzine A [J]. Chemical Science, 2011, 11: 2251-2253. DOI:
10.1039/C1SC00455G.
Pharmacology
Huperzine A has the ability to enhance learning and memory, improve spatial memory, and can be used for age-related dementia, vascular dementia, and other neurodegenerative diseases. Compared with the current anti-AD drugs, huperzine A can go through the blood-brain barrier, with a high oral bioavailability and longer time
inhibition on AChE.
As a highly selective AChE reversible inhibitor, huperzine A can inhibit AChE,
reduce acetylcholine hydrolysis, and improve the level of acetylcholine in the synaptic gap. This inhibition is reversible, lasts for a long time, shows no drug dependence if repeated administration, and does not induce significant liver toxicity.
X-ray diffraction results show that the direct binding of huperzine A to AChE active
sites inhibits the binding of AChE to its substrate.
In addition to the potent inhibition on AChE, huperzine A only shows a weak
inhibitory effect on the butyrylcholinesterase; also protects neurons by inhibiting
oxidative stress, reducing somatostatin, reducing the content of glutamate, decreasing the increased intracellular calcium, and inhibiting neuronal apoptosis; further
improves AD-related cognitive function and reduces the symptoms of AD patients.
Clinical Use
Since 1994, huperzine A has been approved for clinical use in improving memory
and cognitive impairment in old patients with memory loss and dementia. A large
number of domestic clinical studies have found that huperzine A shows therapeutic
effect on learning and cognitive dysfunction of vascular dementia, mental retardation, and schizophrenia patients with mild adverse reactions.
target
AChE | NGF | NMDA receptor
References
[1]. ma xiao-chao, xin jian, wang hai-xue, et al. acute effects of huperzine a and tacrine on rat liver. acta pharmacol ogica sinica, 2003, 24(3):247-250.
[2]. zhong ming qian and ya ke. huperzine a: is it an effective disease-modifying drug for alzheimer's disease? frontiers in aging neuroscience, 2014, 6:216.
[3]. v. rajendran, suo-bao rong, ashima saxena, et al. synthesis of a hybrid analog of the acetylcholinesterase inhibitors huperzine a and huperzine b. tetrahedron letters, 2001, 42: 5359-5361.
[4]. j. r. delfs, d. m. saroff, y. nishida, et al. effects of nmda and its antagonists on ventral horn cholinergic neurons in organotypic roller tube spinal cord cultures. j. neural transm., 1997, 104(1):31-51.
[5]. j. m. zhang and g. y. hu. huperzine a, a nootropic alkaloid, inhibits n-methyl-d-aspartate-induced current in rat dissociated hippocampal neurons. neuroscience, 2001, 105(3):663-9.
[6]. l. zhao, c. b. chu, j. f. li, et al. glycogen synthase kinase-3 reduces acetylcholine level in striatum via disturbing cellular distribution of choline acetyltransferase in cholinergic interneurons in rats. neuroscience, 2013, 255:203-11.
[7]. ellen g. duysen, bin li, sultan darvesh, et al. sensitivity of butyrylcholinesterase knockout mice to (?)-huperzine a and donepezil suggests humans with butyrylcholinesterase deficiency may not tolerate these alzheimer’s disease drugs and indicates butyrylcholinesterase function in neurotransmission. toxicology, 2007, 233:60-69.
[8]. rui wang, han yan and xi-can tang. progress in studies of huperzine a, a natural cholinesterase inhibitor from chinese herbal medicine. acta pharmacologica sinica, 2006, 27:1-26.
