Tacrine structure

M., Cavrini, V. SAR of 9-amino-l,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMEA of tacrine analogues./. Med. Chem. 2000, 43, 2007-2018. 

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. 

Rutaecarpine (46) is the major alkaloid found in Evodia rutaecarpa (Juss.) Benth., and activities relevant to AD have been identified with the extract and with rutaecarpine. Dehydroevodiamine (47), another alkaloid from the same species, inhibited AChE in vitro, and reversed scopolamine-induced memory impairment in rats and increased cerebral blood flow in vivo in cats, a property which would supplement its usefulness in AD. The structures of (46) and (47) and tacrine (28) have been used as templates for the development of a series of synthetic compounds which have been evaluated for their antiChE activity. These were found to be inhibitory against both AChE and BuChE with A -(2-phenylethyl)-A -[(12Z)-7,8,9,10-tetrahydroazepino [2,l- ]quinazolin-12(6//)-ylidene] amine (48) showing higher affinity for BuChE. 

Several inhibitors of AChE have been developed for use in treating Alzheimer s disease, which requires that the drugs readily enter the CNS. These inhibitors are structurally unrelated and vary in their mechanism of inhibition, although all are reversible inhibitors. Tacrine (Cognex) is a monoamine acridine. Donepezil (Aricept) is a piperidine derivative that is a relatively specific inhibitor of AChE in the brain, with little effect on pseudo-ChE in the periphery. Galanthamine (Reminyl) is a tertiary alkaloid and phenanthrene derivative extracted from daffodil bulbs that is a reversible competitive inhibitor of AChE it also acts on nicotinic receptors. 

Figure 7.4. Superimposition ofthe investigated crystal structures of AChE in complex with huperzine (black), tacrine (dark-grey), edrophonium (grey) and decamethonium (light-grey). Only the amino acid residues close to the binding site are displayed.

Recanatini, M., Cavalli, A., Belluti, F., Piazzi, L., Rampa, A., Bisi, A., Gobbi, S., Valenti, P., Andrisano, V., Bartolini, M. and Cavrini, V. (2000) SAR of 9-amino-l,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMEA of tacrine analogues. /. Med. Chem., 43, 2007-2018. 

Sometimes the determination of enzyme crystal structures requires that a substrate be bound to the enzyme. The crystal structures of hCEl in complex with homatro-pine, an anticholinergic drug, tacrine, a cholinesterase inhibitor, or naloxone, an opioid antagonist, have been... 

Bencharit, S., Morton, G. L., Hyatt, J. L., Kuhn, P., KDanks, M. K, Potter, P. M., et al. (2003). Crystal structure of human carboxyles-terase 1 complexed with the alzheimer s drug tacrine from binding promiscuity to selective inhibition. Chemistry 6 Biology, 10, 341-349. 

Fig. 9.4 Chemical structures of tacrine (a) donepezil (b) rivastigmine (c) galantamine (d) huperzine (e) and physostigmine (f)...

Fig. 9.5 Chemical structures of tacrine-based dual binding site acetylcholinesterase (a) bis-tacrine-bearing ketone carbonyl group (b) bis-tacrine-bearing ketone oxalamide group (c) bis-tacrine-bearing ketone ethylenedioxy group (d)...

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