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The Pharmacology and Therapeutic Potential of (-)-Huperzine A

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The Pharmacology and Therapeutic Potential of (-)-Huperzine A Journal of Experimental Pharmacology Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW The pharmacology and therapeutic potential of (-)-huperzine A Maung Kyaw Moe Tun Abstract: (-)-Huperzine A (1) is an alkaloid isolated from a Chinese club moss. Due to Seth B Herzon its potent neuroprotective activities, it has been investigated as a candidate for the treat- ment of neurodegenerative diseases, including Alzheimer’s disease. In this review, we will Department of Chemistry, Yale University, New Haven, CT, USA discuss the pharmacology and therapeutic potential of (-)-huperzine A (1). Synthetic stud- ies of (-)-huperzine A (1) aimed at enabling its development as a pharmaceutical will be described. Keywords: Alzheimer’s, NMDA, neurodegeneration, natural products, synthesis Introduction For personal use only. The search for bioactive metabolites from the plant kingdom has provided many natural products of therapeutic benefit. In spite of the fact that only 5%–15% of the estimated 250,000 plant species have been screened for natural products, approximately 50% of all natural product-derived medicines are obtained from botanical sources.1 Analgesics such as aspirin and morphine, antimalarials such as quinine and artemisinin, and anticancer agents such as paclitaxel and vincristine are well-known examples of plant-derived medicines. The club moss Huperzia serrata has been used for centuries in Chinese folk medicine for the treatment of contusion, strain, swelling, and schizophrenia. In 1986, Liu et al reported the isolation of the alkaloid (-)-huperzine A (1) from the extracts of this moss (Figure 1).2 (-)-Huperzine A (1) was found to possess many of the Journal of Experimental Pharmacology downloaded from https://www.dovepress.com/ by 54.191.40.80 on 07-Jul-2017 pharmacological activities, such as acetylcholinesterase (AChE) inhibition, that were originally associated with the dried moss itself. This discovery ignited a large amount of research aimed at evaluating the scope of huperzine’s pharmacological effects and its clinical potential. Given that (-)-huperzine A (1) is obtained in low yields (0.011%) from the moss, methods to create (-)-huperzine A (1) in the laboratory have also been intensively investigated. This review will summarize the pharmacological effects of (-)-huperzine A (1) and the studies aimed at evaluating its potential for the treatment of neurological diseases. Efforts to develop practical synthetic routes to (-)-huperzine A (1) are described. Pharmacological activities and clinical studies Correspondence: Seth B Herzon Inhibition of acetylcholinesterase Department of Chemistry, Yale University, During neurotransmission, the neurotransmitter acetylcholine (ACh) released from New Haven, Connecticut, 06520, USA Email [email protected] the presynaptic nerve binds to the corresponding receptor. At the postsynaptic submit your manuscript | www.dovepress.com Journal of Experimental Pharmacology 2012:4 113–123 113 Dovepress © 2012 Tun and Herzon, publisher and licensee Dove Medical Press Ltd. This is an Open Access article http://dx.doi.org/10.2147/JEP.S27084 which permits unrestricted noncommercial use, provided the original work is properly cited. Powered by TCPDF (www.tcpdf.org) 1 / 1 Tun and Herzon Dovepress 6 H CH3 CH3H least 50-fold less potent than the natural isomer (-)-isomer. This is expected in light of the X-ray crystallographic H N NH structure of TcAChE complexed with (-)-huperzine A (1), 2 O O 2 NH HN in which there is a strong interaction between the positively charged amino group of (-)-huperzine A (1) and the aromatic CH3 CH3 rings of Trp84 and Phe330 in the active site; (+)-huperzine (+)-huperzine A (−)-huperzine A (1) A (ent-1) may not engage in such interactions with the (ent-1, unnatural enantiomer) enzyme.7 Kozikowski and Tuckmantel have conducted Figure 1 Structures of (-)-huperzine A (1) and (+)-huperzine A (ent-1). extensive structure-activity studies of (-)-huperzine A (1), and identified a single analog with a higher affinity for AChE membrane, acetylcholine is hydrolyzed to acetate and cho- than the natural product.8 The high affinity of -( )-huperzine line by acetylcholinesterase to terminate the relay of the A (1) towards acetylcholinesterase has facilitated the gen- neurotransmission. eration of a number of proposals for its use in the treatment (-)-Huperzine A (1) is a potent and reversible inhibitor of Alzheimer’s disease (AD) and as a pretreatment against of acetylcholinesterase. The 50% inhibitory potency (IC50) organophosphate nerve agents. of (-)-huperzine A (1) against acetylcholinesterase in the rat Although the exact etiology of AD remains unknown, cortex in vitro has been estimated to be 82 nM.3,4 This value the symptoms of AD are associated with cholinergic defi- is greater than that of (±)-donepezil (2, 10 nM; Figure 2), ciencies;9 thus, (-)-huperzine A (1) has been investigated and less than that of tacrine (3, 93 nM). This is consistent as a treatment for Alzheimer’s disease (AD) (vide infra). with the observation that the Ki value of (-)-huperzine A (1) Since 1996, (-)-huperzine A (1) has been approved for the stands at 24.9 nM, between donepezil (12.5 nM) and tacrine treatment of mild-to-moderate AD in China.10 (-)-Huper- (105 nM).3 (-)-Huperzine A (1) shows 900-fold selectivity zine A (1) is widely available in the US nutraceutical towards AChE over butyrylcholinesterase (BuChE). By market. For personal use only. comparison, donepezil and tacrine show lower selectivities Organophosphate nerve agents such as soman and sarin (500- and 0.8-fold, respectively). The selectivity towards are classified by the United Nations as weapons of mass AChE over BuChE may help to alleviate undesirable side destruction.11 They exert their toxicity via irreversible effects associated with inhibition of BuChE. Although the phosphorylation of AChE. The effects of this modification in vitro AChE activity of (-)-huperzine A (1) lies between range from minor symptoms, such as respiratory distress that of donepezil (2) and tacrine (3), the oral AChE inhibitory and hypersalivation, to severe symptoms including seizures potency of (-)-huperzine A (1) is 24 and 180 times higher and incapacitation. At high doses of these agents, death than that of either donepezil (2) or tacrine (3), respectively, ensues. on a molar basis.4 The current method to protect against these war- Lineweaver–Burk analysis establishes (-)-huperzine A (1) fare agents involves pretreating subjects with reversible as a competitive inhibitor of AChE. After sequential incuba- AChE inhibitors such as pyridostigmine (4; Figure 3).12 Journal of Experimental Pharmacology downloaded from https://www.dovepress.com/ by 54.191.40.80 on 07-Jul-2017 tion with (-)-huperzine A (1) and extraction of the metabolite, Pyridostigmine (4) reacts with AChE to form a cabamoylated AChE retains its activity, thereby establishing the reversible enzyme of transient stability. Over the course of a few nature of the AChE–huperzine interaction.5 The absolute ste- hours, this modification is reversed to liberate AChE. This reochemistry of (-)-huperzine A (1) is significant for AChE reversible blocking strategy provides a mechanism to shield inhibition (but not for all pharmacological effects, vide AChE while the nerve agent is metabolized. However, as infra); the unnatural enantiomer (+)-huperzine A (ent-1) is at it cannot pass the blood–brain barrier, pyridostigmine (4) O H CH O NH CH N 3 2 3 O CH3 CH3 N O CH3 O CH O CH3 N 3 N N N O N H CH3 CH3 (±)-donepezil (2) tacrine (3) pyridostigmine (4) (–)-physostigmine (5) Figure 2 Structures of donepezil (2) and tacrine (3). Figure 3 Structures of pyridostigmine (4) and physostigmine (5). 114 submit your manuscript | www.dovepress.com Journal of Experimental Pharmacology 2012:4 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Pharmacology and therapeutic potential of (-)-huperzine A only protects peripheral AChE. It should be noted that O NH2 a related molecule, (-)-physostigmine (5), can cross the N blood–brain barrier; however (-)-physostigmine (5) induces N N undesirable side-effects such as nausea, vomiting, diarrhea, Br and anorexia.13,14 There have been numerous studies assessing the pro- F phylactic potential of (-)-huperzine A (1) against organo- imidazenil (6) phosphates.15–18 One study involved the measurement of Figure 4 Structure of imidazenil (6). LD50 of soman given to mice (subcutaneous injection, SC) pre-administered with (-)-huperzine A (1) (500 µg/kg, senile plaques are β-amyloid (Aβ) fragments, which are intraperitoneal injection, IP) and (-)-physostigmine (5) short peptides containing 36–43 amino acids. β-amyloid (100 µg/kg, intramuscular injection).15 (-)-Huperzine A (Aβ) fragments are formed by proteolysis of the membrane- (1) conferred a 2-fold protective ratio for 6 hours. By com- bound amyloid precursor protein (APP).21 APP is cleaved parison, pretreatment with (-)-physostigmine (5) provided a by at least two pathways, one of which is the α-secretase protective ratio of 1.5 for only 1.5 hours. In a separate study, non-amyloidogenic pathway in which peptidase proteins of soman-induced seizures and subsequent neuropathological disintegrin and metalloprotease families cleave APP into changes of guinea pigs pretreated with (-)-huperzine A (1) soluble α-APP fragments, and then release them into the (500 µg/kg, IP) and pyridostigmine (4) (200 µg/kg, subcu- extracellular media.22 α-APP fragments have been shown taneous injection,
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