SAR Studies of Huperzine

Natural (—)-huperzine A (1) inhibits acetylcholinesterase (AChE) 30 times more potently than its enantiomer (+)-huperzine A, and the racemic form is about two times less potent than the natural form (127,128). In the past ten years, major efforts have been devoted to the preparation of both structurally simplified analogues and derivatives with the tricychc skeleton of huperzine A (1) as a promising lead compound (Fig. 23). 

It thus appears that the structure of huperzine A (1) tolerates little modification without lack of biological activity. Neither heteroatoms or jr-bonds could be omitted, nor could the olefinic methyl substituents be removed or modified without significantly reducing activity. 

The X-ray structures of the complexes of (-l-)-huperzine A (1) and (—)-huperzine B (2) with Torpedo californica AChE were determined at 2.1 and 2.35 A resolution, respectively (152), and compared to the previously determined structure of the (—)-huperzine A complex. Recently, alkylene-linked dimers of 5-amino-5,6,7,8-tetrahydro-quinolinone (hupyridone, 254a), a fragment of huperzine A (1), were shown to serve as more potent inhibitors of AChE than (—)-huperzine A (1) and monomeric 253a. Two dimers, (5, 5 )-(—)-bis(10)-hupyridone [(NjN)- —)-254a] and (S,S)-(—)-bis(12)hupyridone [(5, S)-(—)-254b] containing, respectively, 10 and 12 methylenes in 

Huperzine A (1) has undergone clinical trials in China in patients suffering from various memory disorders, including Alzheimer s disease. Significant effects of huperzine A (1) were noted in these patients in terms of their quality of life and it has become available to numerous individuals for the treatment of memory problems. Since the other pharmacological activities of the various types of Lycopodium alkaloids have been poorly studied, this area should also be developed. Similarly, the biosynthesis of Lycopodium alkaloids has been only preliminarily studied, and the pathways have not been characterized with respect to the intermediates and the relevant enzymes. It will further be of value to elucidate the structural and pharmacological features of more Lycopodium alkaloids. 

Takayama, K. Katakawa, M. Kitajima, H. Seki, K. Yamaguchi, and N. Aimi, Org. Lett. 

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Pharmacology of Huperzine A (1) Total Synthesis of Huperzine A (1) SAR Studies of Huperzine A (1) Conclusions... 

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