Tacrine features

It is interesting that, in addition to its AChE inhibitory eflfects, huperzine A is reported to inhibit NMDA receptor binding and this is also of use in treating AD/ Recently, three compounds, huprine X (42) and its F and Br analogues, huprine Y and huprine Z have been synthesized. These compounds combine the carbobicyclic structural feature of huperzine A (40) with the 4-aminoquinoline skeleton of tacrine (28). All three compounds showed a very strong selectivity for AChE over BuChE and also for human as opposed to bovine AChE and this was demonstrated in vivo as well as in vitro. 

An alternative therapeutic strategy has focused on improving cognitive features of HD, and the effect of this treatment on gene expression has been studied [76], R6/2 mice were treated from 5 weeks old, when they exhibit spatial learning difficulties, with a cocktail of tacrine (an acetylcholine esterase inhibitor, which results in a global increase of brain acetylcholine levels), moclobemide (an antidepressant that inhibits monoamine oxidase A and... 

The pro-cholinergic effect by inhibition of acetylcholinesterase has been proven, but is not the only action of these compounds (Table 1.4). In their review of the subject, Wagstaff and McTavish [1] discussed the therapeutic potential of the different properties of tacrine and recalled that it is impossible to attribute the clinically observed phenomena exclusively to one or other of this drug s properties. Certain features would suggest there is a possible cytoprotector action (anti-glutamate effect [166, 167], an MAO inhibitor effect and a cytoskeleton effect) associated with the symptomatic effect currently in the limelight resulting from the action initially described for neurotransmitters. 

Diaryliodonium salts are proved to be versatile arylating agents due to their advantageous features including easy availability, stability and easy to handle. Recently, Wang et al. utilized an intramolecular [2+2+2] annulation of m-cyano-l-alk5mes 130 with diaryliodonium salts in the construction of polycyclic quinolines 131. This concise method was applied to prepare an Alzheimer drug "Tacrine" 134 (Scheme 29) [45]. 

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