(-)-Huperzine A

Details:

Chemical Properties of (-)-Huperzine A

Cas No.	102518-79-6
PubChem ID	854026	Appearance	White powder
Formula	C15H18N2O	M.Wt	242.32
Type of Compound	Alkaloids	Storage	Desiccate at -20°C
Synonyms	Huperzine A;(-)-huperzine A;(-)-huperazine A;Selagine
Solubility	DMSO : ≥ 100 mg/mL (412.68 mM) *"≥" means soluble, but saturation unknown.
Chemical 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
SMILES	CC=C1C2CC3=C(C1(CC(=C2)C)N)C=CC(=O)N3
Standard InChIKey	ZRJBHWIHUMBLCN-YQEJDHNASA-N
Standard 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
General tips	For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging	1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment.
Shipping Condition	Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Source of (-)-Huperzine A

1 Lycopodium sp.

Biological Activity of (-)-Huperzine A

Description	(-)-Huperzine A is a naturally occurring potent reversible AChE inhibitor that penetrates the blood-brain barrier, it also has several neuroprotective effects including modification of beta-amyloid peptide, reduction of oxidative stress, anti-inflammatory, anti-apoptotic and induction and regulation of nerve growth factor.
Targets	AChE | NGF | NMDA receptor
In vivo	A combination of [+] and [-]-Huperzine A improves protection against soman toxicity compared to [+]-Huperzine A in guinea pigs.[Pubmed: 23123250] Chem Biol Interact. 2013 Mar 25;203(1):120-4. The neuropathologic mechanisms after exposure to lethal doses of nerve agent are complex and involve multiple biochemical pathways. Effective treatment requires drugs that can simultaneously protect by reversible binding to the acetylcholinesterase (AChE) and blocking cascades of seizure related brain damage, inflammation, neuronal degeneration as well as promoting induction of neuroregeneration. (-)-Huperzine A ([-]-Hup A), is a naturally occurring potent reversible AChE inhibitor that penetrates the blood-brain barrier. It also has several neuroprotective effects including modification of beta-amyloid peptide, reduction of oxidative stress, anti-inflammatory, anti-apoptotic and induction and regulation of nerve growth factor. METHODS AND RESULTS: Toxicities at higher doses restrict the neuroporotective ability of (-)-Huperzine A for treatment. The synthetic stereoisomer, [+]-Hup A, is less toxic due to poor AChE inhibition and is suitable for both pre-/post-exposure treatments of nerve agent toxicity. [+]-Hup A block the N-methyl-D-aspartate (NMDA)-induced seizure in rats, reduce excitatory amino acid induced neurotoxicity and also prevent soman induced toxicity with minimum performance decrement. Unique combinations of two stereo-isomers of Hup A may provide an excellent pre/post-treatment drug for the nerve agent induced seizure/status epilepticus. We investigated a combination of [+]-Hup A with a small dose of (-)-Huperzine A ([+] and (-)-Huperzine A) against soman toxicity. Our data showed that pretreatment with a combination [+] and (-)-Huperzine A significantly increased the survival rate and reduced behavioral abnormalities after exposure to 1.2 × LD(50) soman compared to [+]-Hup A in guinea pigs. In addition, [+] and (-)-Huperzine A pretreatment inhibited the development of high power of EEG better than [+]-Hup A pretreatment alone. CONCLUSIONS: These data suggest that a combination of [+] and (-)-Huperzine A offers better protection than [+]-Hup A and serves as a potent medical countermeasure against lethal dose nerve agent toxicity in guinea pigs.

Protocol of (-)-Huperzine A

Structure Identification

Org Lett. 2013 Feb 15;15(4):882-5. A novel synthesis of (-)-huperzine A via tandem intramolecular aza-Prins cyclization-cyclobutane fragmentation.[Pubmed: 23346936] The acetylcholinesterase inhibitor (-)-Huperzine A was synthesized from (S)-4-hydroxycyclohex-2-enone in 17 steps by a route that involved two cyclobutane fragmentations. The first of these employed a retro-aldol cleavage to generate the α-pyridone ring of huperzine A, and the second invoked a novel intramolecular aza-Prins reaction in tandem with stereocontrolled scission of a cyclobutylcarbinyl cation to create the aminobicyclo[3.3.1]nonene framework of the natural alkaloid. Org Lett. 2012 Sep 7;14(17):4446-9. An efficient total synthesis of (-)-huperzine A.[Pubmed: 22900755] 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.

Preparing Stock Solutions of (-)-Huperzine A

	1 mg	5 mg	10 mg	20 mg	25 mg
1 mM	4.1268 mL	20.6339 mL	41.2677 mL	82.5355 mL	103.1694 mL
5 mM	0.8254 mL	4.1268 mL	8.2535 mL	16.5071 mL	20.6339 mL
10 mM	0.4127 mL	2.0634 mL	4.1268 mL	8.2535 mL	10.3169 mL
50 mM	0.0825 mL	0.4127 mL	0.8254 mL	1.6507 mL	2.0634 mL
100 mM	0.0413 mL	0.2063 mL	0.4127 mL	0.8254 mL	1.0317 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of (-)-Huperzine A

1. Transepithelial transport of a natural cholinesterase inhibitor, huperzine A, along the gastrointestinal tract: the role of ionization on absorption mechanism. Planta Med. 2013 Mar;79(3-4):259-65. doi: 10.1055/s-0032-1328128. Epub 2013 Jan 23.
Abstract
Three different models were used to evaluate the intestinal permeability of huperzine A, including in vitro Caco-2 and parallel artificial membrane permeation assay models and the ex vivo Ussing chamber model, in which results suggest the permeability rate was strongly ionization dependent and increased with elevation of the donor medium PH. Though the majority of huperzine A passes through intestinal border through passive transcellular diffusion, a small fraction depending on the degree of ionization is absorbed by the paracellular route.

2. The effects of huperzine A on gastrointestinal acetylcholinesterase activity and motility after single and multiple dosing in mice. Exp Ther Med. 2013 Mar;5(3):793-796. Epub 2013 Jan 4.
Abstract
Huperzine A, an AchEl used to treat cognitive deterioration associated with AD, has side effects associated with increased cholinergic activity in the gastrointestinal system. Following oral administration of huperine A to mice, a single dose significantly inhibited the AChE activity in the stomach and duodenum and significantly increased the gastrointestinal motility; while multiple doses caused no significant changes in both.

3. Synergistic Effect and Mechanism of Cineole and Terpineol on In-vitro Transdermal Delivery of Huperzine A from Microemulsions. Iran J Pharm Res. 2013 Spring;12(2):271-80.
Abstract
Cineole and terpineol synergistically increased the transdermal delivery of huperzine from microemulsions in Franz-type diffusion cells through increasing the partition and diffusion coefficients of huperzine A, in which ATR-FTIR analysis revealed the mechanism of the synergistic effects was due to increasing the disorderliness and fluidity of SC lipid alkyl chains, disrupting the structure of keratin in SC, and extracting SC lipids.

4. Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease. Acta Pharmacol Sin. 2013 Jul;34(7):976-82. doi: 10.1038/aps.2013.7. Epub 2013 Apr 29.
Abstract
Huperzine A is a novel reversible and selective AchE inhibition that is isolated from Chinese herb Hyperzia serrate (Thunb) Trev.

5. Huperzine a for Alzheimer's disease: a systematic review and meta-analysis of randomized clinical trials. PLoS One. 2013 Sep 23;8(9):e74916. doi: 10.1371/journal.pone.0074916. eCollection 2013.
Abstract
As a drug extracted from a Chinese herb to treat Alzheimer’s disease, huperzine A was evaluated for its beneficial and harmful effects.

 

References on (-)-Huperzine A

A novel synthesis of (-)-huperzine A via tandem intramolecular aza-Prins cyclization-cyclobutane fragmentation.[Pubmed:23346936]

Org Lett. 2013 Feb 15;15(4):882-5.

The acetylcholinesterase inhibitor (-)-Huperzine A was synthesized from (S)-4-hydroxycyclohex-2-enone in 17 steps by a route that involved two cyclobutane fragmentations. The first of these employed a retro-aldol cleavage to generate the alpha-pyridone ring of huperzine A, and the second invoked a novel intramolecular aza-Prins reaction in tandem with stereocontrolled scission of a cyclobutylcarbinyl cation to create the aminobicyclo[3.3.1]nonene framework of the natural alkaloid.

Total synthesis of (-)-huperzine A.[Pubmed:19873983]

Org Lett. 2009 Nov 19;11(22):5354-6.

The total synthesis of (-)-Huperzine A was accomplished in 23 steps from a commercially available anhydride. Our synthetic route features a facile construction of the bicyclo[3.3.1] skeleton equipped with proper functionalities to introduce the remaining substructures.

A combination of [+] and [-]-Huperzine A improves protection against soman toxicity compared to [+]-Huperzine A in guinea pigs.[Pubmed:23123250]

Chem Biol Interact. 2013 Mar 25;203(1):120-4.

The neuropathologic mechanisms after exposure to lethal doses of nerve agent are complex and involve multiple biochemical pathways. Effective treatment requires drugs that can simultaneously protect by reversible binding to the acetylcholinesterase (AChE) and blocking cascades of seizure related brain damage, inflammation, neuronal degeneration as well as promoting induction of neuroregeneration. [-]-Huperzine A ([-]-Hup A), is a naturally occurring potent reversible AChE inhibitor that penetrates the blood-brain barrier. It also has several neuroprotective effects including modification of beta-amyloid peptide, reduction of oxidative stress, anti-inflammatory, anti-apoptotic and induction and regulation of nerve growth factor. Toxicities at higher doses restrict the neuroporotective ability of [-]-Hup A for treatment. The synthetic stereoisomer, [+]-Hup A, is less toxic due to poor AChE inhibition and is suitable for both pre-/post-exposure treatments of nerve agent toxicity. [+]-Hup A block the N-methyl-D-aspartate (NMDA)-induced seizure in rats, reduce excitatory amino acid induced neurotoxicity and also prevent soman induced toxicity with minimum performance decrement. Unique combinations of two stereo-isomers of Hup A may provide an excellent pre/post-treatment drug for the nerve agent induced seizure/status epilepticus. We investigated a combination of [+]-Hup A with a small dose of [-]-Hup A ([+] and [-]-Hup A) against soman toxicity. Our data showed that pretreatment with a combination [+] and [-]-Hup A significantly increased the survival rate and reduced behavioral abnormalities after exposure to 1.2 x LD(50) soman compared to [+]-Hup A in guinea pigs. In addition, [+] and [-]-Hup A pretreatment inhibited the development of high power of EEG better than [+]-Hup A pretreatment alone. These data suggest that a combination of [+] and [-]-Hup A offers better protection than [+]-Hup A and serves as a potent medical countermeasure against lethal dose nerve agent toxicity in guinea pigs.

An efficient total synthesis of (-)-huperzine A.[Pubmed:22900755]

Org Lett. 2012 Sep 7;14(17):4446-9.

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 beta-elimination and the accompanying Wagner-Meerwein rearrangement are of particular interest.

Description

(-)-Huperzine A (Huperzine A), an active Lycopodium alkaloid extracted from traditional Chinese herb, is a potent, selective and reversible acetylcholinesterase (AChE) inhibitor and has been widely used in China for the treatment of Alzheimer's disease (AD).

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