Galanthamine acetylcholinesterase

Galanthamine (23) is an alkaloid extracted from the common snowdrop Galanthus nivalis. This compound is a long-acting, competitive AChE inhibitor which appears to be somewhat more specific for acetylcholinesterase than plasma butyrylcholinesterase (132). It is well tolerated during long-term treatment (133) and is being evaluated clinically for AD (134). 

The acetylcholinesterase inhibitor tacrine (64) was approved for the treatment of mild-to-moderate SDAT in the United States in 1993 followed by several other countries. The acetylcholinesterase inhibitor galanthamine (65), which has long been in clinical use in Austria for the treatment of indications such as facial neuralgia and residual poliomyelitis paralysis, has also been approved for use in... 

Greenblatt HM, Kryger G Lewis T, Sihnan 1, Sussman JL. (1999) Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution. FEES Lett 463 321-326. 

Bores GM, Huger FP, Petko W, Pharmacological evaluation of novel Alzheimer disease therapeutics, acetylcholinesterase inhibitors related to galanthamine. Am Soc Pharmacol Exp Therapeut 277 72 —1996. 

Oxazocine 119 is a synthetic derivative of galanthamine 162. The latter is a tertiary alkaloid, isolated from amaryllidaceae, which is a central acting competitive and reversible inhibitor of acetylcholinesterase that enhances cognitive functions in Alzheimer s patients. However, oxazocine 119 showed a decreased potency as an acetylcholinesterase inhibitor and a marked selectivity with respect to butyrylcholinesterase, probably because butyrylcholinesterase accommodates steric bulk around the catalytic site, better than acetylcholinesterase <2003BML2389>. 

An example of use of the conglomerate Nar-wedine (59) in the synthesis of a natural product Galanthamine (61) which is din Amarylli-daceae alkaloid and has been used clinically for 30 years for neurological illnesses (98). More recently it has been approved for the use in the treatment of Alzheimer s disease (AD) (99). Galanthamine acts to inhibit acetylcholinesterase (AChE), thus increasing the levels... 

Mary, A., Renko, D. Z., Guillou, C., Thai, C. Potent acetylcholinesterase inhibitors design, synthesis, and structure-activity relationships of te-interacting ligands in the galanthamine series. Bioorg. Med. Chem. 1998, 6, 1835-1850. 

Sramek, J.J., Frackiewicz, E.J., and Cutler, N.R., Review of the acetylcholinesterase inhibitor galanthamine. Expert Opin. Investig. Drugs, 9, 2393, 2000. 

Galanthamine (261) has been prominent in the popular and general scientific press because of its purported usefulness in healing Alzheimer s disease, presumably due to its acetylcholinesterase and muscarinic activity. 

Galanthamine is a natural alkaloid and a potent acetylcholinesterase inhibitor. Recognizing the potential to access this rigid polycyclic core through a biomimetic oxidative coupling/Michael addition, Shair and coworkers developed a highly efficient diversity-oriented synthesis based on this scaffold (Scheme 21.16) [96]. A library of 2527 compounds was prepared on the aforementioned macrobeads... 

The alkaloid galanthamine (169) has been obtained from various Amaryllidaceae species including daffodils, the red spider lily Lycoris radiata) and the Caucasian snowdrop (Galanthus woronowii). Its effectiveness as a centrally acting, selective, reversible and competitive inhibitor of acetylcholinesterase has resulted in galanthamine being introduced into the clinic in both the USA and Europe for the symptomatic treatment of mild to moderate forms of Alzheimer s disease [57]. These and various other intriguing feamres of this alkaloid have prompted extensive synthetic studies of it [57]. 

Galanthamine also blocks acetylcholine estaase activity. One of the new applicaticms of galanthamine is in a treatment of Alzheimer s disease (AD). Moreover, this natural (and presently also synthetically driven) alkaloid can be used in decreasing negative side effects caused by applications of nondepolarizing alkaloids, for example, those of tubocurarine. Acetylcholinesterase activity is reported to depress and inhibit by lycorine and its derivatives. Lycorine is an object of therapeutic approaches to cure AD and decrease a level of esterase activity, Other alkaloids from the Amaiyllidaceae plant family are probably useful for these purposes and are being researched. 

Sanguinine (81) has a more potent acetylcholinesterase inhibitory activity than galanthamine (75) due to an extra hydroxyl group available for potential interaction with acetylcholinesterase (93,555). Sanguinine, in turn, is 10-fold more selective than galanthamine for acetylcholinesterase (AChE) vs. butyrylcholinesterase (BuChE)... 

Galanthamine para- ortho Narcissus pseudonarcissus Leucojum aestivum Galanthus niveali Galanthus elewesii Pancratium maritimum acetylcholinesterase inhibitor, treatment for Alzheimer s disease [4,8-10]... 

For example, acetylcholinesterase inhibitor galanthamine and anticancerous agent narciclasine and crinine, could be produced commercially by such newly designed plant breeding programs. 

The alkaloid (—)-galanthamine, isolated from Caucasian snow-drop Galanthus woronowii) and other plant sources, is a competitive and reversible acetylcholinesterase inhibitor and an allosteric modulator of the neural nicotine receptors for acetylcholine. Galanthamine hydrobromide (commercially available as Razadyne) finds application in the treatment of symptoms of Alzheimer s disease [101]. Since the isolation of galanthamine (256) from natural sources is quite expensive, several total syntheses have been developed to date. The synthetic strategy to galanthamine (256) developed by Cho et al. [102] includes a domino Stille/Diels-Alder reaction as the key step (Scheme 14.39). 

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