In TCM a prescription prepared from Huperzia serrata (Thunb.) Trevis. (Lycopodiaceae) has been a treatment for memory loss. Of the alkaloids isolated from Huperzia serrata, huperzine A has been extensively studied for pharmacological and clinical effects in relation to treatment of cognitive disorders.
A range of studies in animals have shown this alkaloid to improve memory-retention processes in cognitively impaired aged and adult rats and to attenuate cognitive deficits in chronically hypoperfused rats and in gerbils following ischemia. The principal mechanism of action thought to be responsible for the cognitive-enhancing effects of huperzine A is modulation of cholinergic function by inhibition of cholinesterase; it reversibly inhibits acetylcholinesterase both in vitro and in vivo. Huperzine A is more selective for acetylcholinesterase than butyrylcholinesterase, was less toxic than the synthetic acetylcholinesterase inhibitors donepezil and tacrine and significantly improved memory and behaviour in Alzheimer’s disease patients in a multicentre, double-blind trial. In phase IV clinical trials in China, huperzine A improved memory in elderly, Alzheimer’s disease and vascular dementia patients, with limited adverse effects. Pharmacokinetic studies have indicated that huperzine A is rapidly absorbed, widely distributed in the body and eliminated at a moderate rate.
In addition to cholinesterase inhibition, other effects may contribute to the cognitive benefits of this remedy. Huperzine A also favourably affects other neurotransmitter systems to improve memory. It was also neuroprotective against β-amyloid peptide, oxygen-glucose deprivation, free-radical-induced cytotoxicity and glutamate and it acts as an NMDA receptor antagonist in the cerebral cortex. The enantiomers of huperzine A concentration-dependently inhibit NMDA receptor binding without stereoselectivity, although stereo selectivity is reported in the inhibition of acetylcholinesterase, with the (+)-isomer of huperzine A being less potent than the natural (-)-isomer. Huperzine A is also suggested to attenuate apoptosis by inhibiting the mitochondria-capase pathway and to have neu-rotrophic effects. Huperzine B, also from Huperzia serrata, attenuates H2O2-and oxygen-glucose-deprivation-induced injury in the rat pheochromocytoma cell line PC 12, indicating that it has a neuroprotective action.
Huperzine A appears to be therapeutically advantageous over some other known cholinesterase inhibitors since it is a potent, reversible and relatively selective inhibitor of acetylcholinesterase, it shows other activities that may be relevant in alleviating cognitive dysfunction and it has shown efficacy in clinical trials in cognitively impaired patients with few adverse effects. It is therefore not surprising that the structures of huperzines A and B have been used as templates for the synthesis of new compounds, with the aim of developing potentially new drugs with improved efficacy and safety.
Analogues of huperzine A synthesised to achieve 5-substitution with either a hydroxyl group, a fluoro group or an acetoxyl group were assessed for their anti-acetylcholinesterase activity in vitro. The acetylcholinesterase inhibitory activities of these 5-substituted huperzine A analogues were also less potent than huperzine A when tested in vitro, indicating that the C-5 amino group in huperzine A (which can form a quaternary ammonium under physiological conditions to imitate acetylcholine) is an important structural feature for acetylcholinesterase inhibition. Other compounds synthesised are the (E)- and (Z)-5-desamino huperzine A derivatives, which, although more potent than the 5-fluoro and 5-hydroxyl derivatives in the inhibition of acetylcholinesterase in vitro, were still less potent than huperzine A. Another synthetic derivative of huperzine A, (-)-dimethylhuperzine A (dimethylhuperzine A), showed acetylcholinesterase inhibitory activity comparable to (-)-huperzine A, and although the enantiomer (+)-dimethylhuperzine A was inactive against acetylcholinesterase activity, both enantiomers were equally effective in protecting against glutamate-induced neurotoxicity. Analogues of huperzine B have also been synthesised with the aim of improving acetylcholinesterase inhibitory potency, but although some of these analogues are reported to be up to four-fold more potent than huperzine B, they were not as potent as huperzine A in the inhibition of acetylcholinesterase.
Other huperzine A hybrids that have been synthesised include structural features of both huperzine A and E2020 (donepezil). These hybrid compounds were synthesised with the aim of enabling an interaction between the 5,6,7,8-tetrahy-droquinolinone of huperzine A and the active site of acetylcholinesterase, and an interaction between the benzyl piperidine of E2020 and the peripheral binding site of acetylcholinesterase, but these derivatives were less potent than E2020 in the inhibition of acetylcholinesterase in vitro.