Bivalent Ligands Derived from Huperzine A as Acetylcholinesterase Inhibitors

Abstract

The naturally occurring alkaloid Huperzine A (HupA) is an acetylcholinesterase (AChE) inhibitor that has been used for centuries as a Chinese folk medicine in the context of its source plant Huperzia Serrata. The potency and relative safety of HupA rendered it a promising drug for the ameliorative treatment of Alzheimer's disease (AD) vis-à-vis the "cholinergic hypothesis" that attributes the cognitive decrements associated with AD to acetylcholine deficiency in the brain. However, recent evidence supports a neuroprotective role for HupA, suggesting that it could act as more than a mere palliative. Biochemical and crystallographic studies of AChE revealed two potential binding sites in the active-site gorge of AChE, one of which, the "peripheral anionic site" at the mouth of the gorge, was implicated in promoting aggregation of the beta amyloid (Abeta) peptide responsible for the neurodegenerative process in AD. This feature of AChE facilitated the development of dual-site binding HupA-based bivalent ligands, in hopes of concomitantly increasing AChE inhibition potency by utilizing the "chelate effect", and protecting neurons from Abeta toxicity. Crystal structures of AChE allowed detailed modeling and docking studies that were instrumental in enhancing the understanding of underlying principles of bivalent inhibitor-enzyme dynamics. This monograph reviews two categories of HupA-based bivalent ligands, in which HupA and HupA fragments serve as building blocks, with a focus on the recently solved crystallographic structures of Torpedo californica AChE in complex with such bifunctional agents. The advantages and drawbacks of such structured-based drug design, as well as species differences, are highlighted and discussed.

Cholinesterases, a Target of Pharmacology and Toxicology

“…Tyr 70, Asp 72, Tyr 121, Trp 279 and Tyr 334 amino acids residues are the most significant residues in the peripheral anionic site 48 . As described in the following chapters, the peripheral anionic site is a target for a number of toxins and also promising drugs 49,50 . It probably plays an important role in the development of Alzheimer's disease.…”

Synthesis and Multitarget Biological Profiling of a Novel Family of Rhein Derivatives As Disease-Modifying Anti-Alzheimer Agents

“…dual binding site AChE inhibitors (AChEIs), emerged some years ago as a promising source of multi-target anti-Alzheimer compounds, inasmuch as they should be endowed at least with potent anticholinesterase and Aβ anti-aggregating effects. [21][22][23][24][25][26][27][28][29] Moreover, the multi-target profile of these compounds can be enlarged by introducing pharmacophoric moieties that are also suitable for separate interactions with additional targets of interest other than AChE and Aβ. Two major challenges in the design and therapeutic potential of multi-target anti-Alzheimer agents are the choice of the targets to be hit and the potency of the compounds at the different targets.…”

In vitro Anticholinesterase Activity of Various Alkaloids

“…AChE inhibitors diminish the rate at which acetylcholine (ACh) is broken down and hence increase the concentration of ACh in the brain (Shen, 2004;Samanta et al, 2006). The commercially available AChE inhibitors such as tacrine, donepezil, rivastigmine, or galanthamine may help to prevent, for a limited time, some symptoms from becoming worse for some people in the early and middle stages of the disease (Luckmann, 2006;Haviv et al, 2007).…”