Acetylcholinesterase alkaloid reversible inhibitor

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>. 

I Tertiary alkaloid, reversible acetylcholinesterase inhibitor, also potentiates the action of ACh at nicotinic receptors. 

The physiological activity of acetylcholine relies on local release, stimulation of the receptor, then rapid hydrolysis (deacetylation) by acetylcholinesterase, which results in deactivation. The indole alkaloid physostigmine, from the West African calabar bean, and the relatively simple synthetic compound pyridostigmine, which has a more obvious relationship to choline, are reversible inhibitors of acetylcholinesterase. Controlled inhibition of the enzyme by such drugs, which results in a build-up of ACh, is useful in conditions such as myasthenia gravis, a muscle weakness, which is caused by insufficient production of ACh. 

Galantamine, unlike the other anticholinesterases in clinical use, is derived from the alkaloids from the daffodil and snowdrop family. It is a reversible, competitive inhibitor of acetylcholinesterase with some inhibitory action on butyryl cholinesterase. It is also an agonist at nicotinic receptor sites. Although a clinically effective drug, galantamine frequently causes gastrointestinal side effects. 

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]. 

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). 

Huperzine, an alkaloid from the plant Huperzia serrata, is a potent and highly selective, reversible acetylcholinesterase inhibitor. 

Huperzine A (49) is a sesquiterpene alkaloid isolated from a traditional Chinese herbal remedy, Huperzia serrata ( Qian Ceng Ta ) in 1986 [128], This compound has been proved to be a potent, selective and reversible acetylcholinesterase (AChE) inhibitor, and demonstrated memory enhancement and neuroprotective functions in clinical trials as a therapeutic against Alzheimer s disease (AD) in the People s Republic of China [129, 130], In 2004, a phase II clinical trial focused on its cognitive function was initiated by the National Institute on Aging (NIA) in the United States [131], ZT-1 (50), considered more selective than huperzine A, was developed as a semi-synthetic derivative of 49 by cooperation of the Shanghai Institute of Materia Medica and Debiopharm of Switzerland and is currently... 

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