Huperzine

The 1.3-allylic diacetate 135 can be used for the formation of the methy-lenecyclopentane 137 with the dianionic compound 136(86]. The cyclohexa-none-2-carboxylate 138 itself undergoes a similar annulation with the 1,3-allylic diacetate 135 to form the methylenecyclohexane derivative 139(90]. The reaction was applied as a key step in the synthesis of huperzin A[91]. On the other hand. C- and 0-allylations of simple J-dikctones or. 1-keto esters take place, yielding a dihydropyran 140(92]. 

Chemistry, pharmacology, and clinical efficacy of the Chinese nootropic agent huperzine A, alkaloid from Hupenia sermta with annulated 2-pyridone and l-amino-3-methyl-9-ethylidenebicyclo[3.3.l]nona-2,6-diene fragments 99ACR641. 

In the synthesis of fluorinated analogs of the acetylcholinesterase inhibitor, huperzine A, it was necessary to accomplish reductive elimination of the diol 15-D to 15-E. Of the methods for diol reduction, which seems most compatible with the other functional groups in this compound ... 

The group of Terashima [35] developed an asymmetric domino Michael/aldol process using the chinchona alkaloid (-)-cinchonidine (2-103), to prepare an intermediate for the synthesis of the natural product (-)-huperzine A (2-102) [36] (Scheme 2.22). 

Although initial studies suggest potential effectiveness of huperzine A, it has not been adequately evaluated for treatment of AD. 

Traditionally, plants are a rich source of AChE inhibitors. People from the Caucasus used bulbs of snowdrops Galanthus sp.) to treat forgetfulness [25]. The active compound in this plant has been isolated and called galanthamine. Other plant-derived AChE inhibitors used for treatment of Alzheimer s disease include Huperzine A from Huperzia serrata and Rivastigmine (Excelon). The latter is a derivative from physostigmine isolated from the calabar bean, Physos-tigma vmmosum. 

IC50 curves were also recorded for various other inhibitors and the corresponding IC50 values were calculated. The determined IC50 values of 9-aminoacridine, galanthamine, gallamine, (—)-Huperzine A and thioflavin T were 0.12 pM, 0.38 pM, 6.4 pM, 0.46 pM, and 3.2 pM, respectively. It was difficult to compare these values with comparable values in literature since often different types of AChE, or AChE isolated from different organisms were used and different assay conditions were applied. However, the relative activities of the used inhibitors compared well with those reported in literature, except for (—)-huperzine A, which was found to be relatively less active then was expected. 

Coleman BR, Ratcliffe R, Oguntayo S, Shi X, Doctor B, Gordon R, Nambiar M. (2008) [-i-]-Huperzine A treatment protects against A-methyl-d-aspartate-induced seizure/status epilepticus in rats. Chembiol Interact 175 387-395. 

Bai DL, Tang XC, He XC. (2000) Huperzine A, a potential therapeutic agent for treatment of Alzheimers disease. CurrMed Chem 7 355-374. 

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. Pharmacol BiochemBehav 75 675-686. 

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. J Neural Transm 116 457 65. 

Wang R, Tang XC. (2005) Neuroprotective effects of huperzine A. Neurosignals 14 71-82. 

Walsh S, Aisen P, Little J. (2008) An update on huperzine A as a treatment for Alzheimer s disease. Expert Opin Investig Drugs 17 209-215. 

It is interesting that, in addition to its AChE inhibitory eflfects, huperzine A is reported to inhibit NMDA receptor binding and this is also of use in treating AD/ Recently, three compounds, huprine X (42) and its F and Br analogues, huprine Y and huprine Z have been synthesized. These compounds combine the carbobicyclic structural feature of huperzine A (40) with the 4-aminoquinoline skeleton of tacrine (28). All three compounds showed a very strong selectivity for AChE over BuChE and also for human as opposed to bovine AChE and this was demonstrated in vivo as well as in vitro. 

Lu WH, Shou J, Tang XC, Improving effect of huperzine A in aged rats and adult tats with experimental cognitive impairment, Acta Pharm Sinica 9 11—15, 1988. 

Xiao XQ, Zhang HY, Tang XC, Huperzine A attenuates amyloid fl-peptide fragment 25-35-induced apoptosis in rat cortical neutons via inhibiting reactive oxygen species formation and caspase-3 activation, J Neurosci Res 67 30—36, 2002. 

Zhang Z, Wang X, Chen Q, Clinical efficacy and safety of huperzine alpha in treatment of mild to moderate Alzheimer s disease, a placebo-controlled, doubleblind, randomised trial, Chin Med/ 82 941-944, 2002. 

Zhou GC, Zhu DY, Synthesis of 5-substituted analogues of huperzine A, Bioorg... 

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