AChE inhibitory

Compound 10 was evaluated for anti-bacterial activity and acetylchohnesterase (AChE) inhibitory activities. This compound was foimd to be inactive in antibacterial assay and exhibited AChE inhibitory activity with an ICj, value of 67 pM. Acetylcholine serves as a neurotransmitter in the central and peripheral nervous system. Acetylcholinesterase (AChE) stops the function of acetylcholine by its... 

Compound 11 showed AChE inhibitory activity with an ICj, 19 pM. and weak antifimgal activity against Candida albicans with a minimum inhibitory concentration (MIC) value of 23 pg/ml. 

A second line of research in this area has demonstrated an AchE inhibitory effect of withanolides in vitro. More studies are needed to assess their exact mechanisms of action and extent of utility in AD as human trials are lacking. Nevertheless, these investigations do demonstrate the potential for a therapeutic role of withanolides/withanamides in both protecting against amyloid neuronal pathology and in AchE inhibition. ... 

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. 

Most other alkaloids shown to have AChE inhibitory activity have been isolated from plants used in traditional medicine. Coptis chinensis Franch has been used in TCM for several conditions including age-related cognitive and memory decHne. Some alkaloids found in this species e.g. berberine (43), coptisine (44) and palmatine (45) are reported to also be antiChE. Coptis chinensis extract improved a scopolamine-induced learning and memory deficit in rats and this is likely to be due to the alkaloids present thus raising ACh levels. Berberine (43) has been shown to selectively inhibit AChE compared with Bu ChE and it has been shown to improve scopolamine-induced amnesia in rats. ... 

Of the many types of phenolic compounds, not many have been shown to possess AChE inhibitory activity. The root and stem bark of Magnolia officinalis Rehd. Et Wils. contains the biphenolic lignans, honokiol (72) and magnolol (73). Both lignans increased ChAT activity and inhibited AChE activity in vitro, and increased hippocampal ACh release in vivo) These two compounds also appeared to have antioxidant antiinflammatory... 

The AChE inhibitory properties of the coumarins scopoletin (75) and scopolin (76) were discovered by an interesting in silico approach. A model 3-dimensional pharmacophore was constructed, using a database of known inhibitors and their interaction with the AChE from Torpedo californica. The model was then used to predict likely inhibitors from a large database of those whose molecular coordinates were known. (75) and (76) were predicted and then isolated from Scopolia carniolica and tested in the Ellman assay. Results showed that (75) was much more active than the glucoside (76) but it was 2.5 orders of magnitude weaker than galantamine. Scopoletin also showed activity in vivo when given to rats. 

The furanocoumarins xanthotoxin (77) and isopimpinellim (78) from roots of A. acutiloba displayed significant AChE inhibitory activity with IC50 values of 0.58 xM and 0.32 xM respectively." Prenylated coumarins itom. Angelica spp. had only weak activity, with decursinol (79) giving the highest activity (IC50 value 28 xM)." ... 

Some azocine derivatives, synthesized via this protocol, exhibited acetylcholinesterase (AChE) inhibitory activity (06MI7205). 

In vitro studies have demonstrated that ZT-1 is a potent and selective AChEI in rat cortex homogenate and in red blood cell AChE from different species (rat, bovine, and human). In contrast, ZT-1 presents a much weaker inhibitory activity on rat BuChE. In vitro, the AChE inhibitory effect of ZT-1 and HA is in the same range and slightly stronger than tacrine. 

Extracts of some amaryllids, as well as alkaloids isolated therefrom, have exhibited various biological activities. These activities cover central nervous system, antitumor, antiviral, antibacterial, anti-inflammatory and antiparasitic conditions 8, 18, 52, 53, 54). However, the more recently demonstrated potent anticancer activity of pancratistatin 14 and the selective, reversible acetylcholinestrase (ACHE) inhibitory activity of galanthamine 5 has fuelled the search for bioactive Amaryllidaceae alkaloids toward the development of antitumor and anti-Alzheimer s drags 55). 

Diazapentacyclic analogs. Kumar et al. [171] synthesized and evaluated diazapentacyclic analogs for their acetylcholinesterase (AChE) inhibitory activity. The pentacyclic analogs were synthesized by one-pot three-component domino reactions in a micro-wave synthesizer. Most of the compounds exhibited moderate to good AChE inhibitory activity. 

Salvia sclareoides (Rosmarinic acid). Salvia sclareoides extracts showed acetylcholinesterase (AChE) inhibitory activity. Rosmarinic acid is present in the extracts where luteolin 4 -O-glucoside, luteolin 3, 7-di-O-glucoside, and luteolin 7-0- (6 -O-acetylplucoside) were also identified. Rosmarinic acid is the only explicit binder for AChE [262],... 

TABLE 29.2 Compounds Designed, Synthesized, and Assayed for Their AChE Inhibitory Activity ... 

For the parasitic flatworms these include acetylcholine (ACh) (inhibitory), serotonin (5-HT) (excitatory) and glutamate (excitatory in cestodes). Other active substances with weaker candidacies are dopamine (excitatory in trematodes), noradrenaline (mixed action depending on trematode species) and histamine (excitatory in cestodes). Based on the circumstantial evidence of immuno-cytochemical studies and by analogy with other organisms, it is reasonable to hypothesize that certain neuropeptides (e.g., NPF-related peptides, among others) may also have effects on the neuromuscular system of parasitic flatworms, but the functional studies to demonstrate this have yet to be done. 

In parasitic flatworms, 5-HT serves a variety of functions from control of carbohydrate metabolism to intra- and interorganism (host-parasite) communication (36). Rhythmical movement is stimulated by 5-HT and related indoleamines (e.g., lysergic acid diethylamide) (7,8,37). This stimulatory effect, like the ACh inhibitory effect, can be obtained in the absence of the central ganglia suggesting a peripheral site of action (37). The stimulation of motility (increased contraction amplitude and frequency) in vitro suggests that 5-HT or a closely related indoleamine is an excitatory transmitter in both the trematodes F. hepatica (9, 37, 38), S. mansoni (11, 12, 39, 40), Clonorchis sinensis... 

The first evidence for enantioselectivity in the reaction of organophosphorus compounds with AChE was reported by Michel who noted a biphasic inhibition on incubation of AChE with racemic sarin. Shortly afterwards, Aaron et reported enantioselective AChE inhibitory activity for the resolved isomers of O-ethyl S-(2-ethylthioethyl) ethylphosphonothionate. Subsequent isolation, or partial resolution, of the enantiomers of sarin, soman, tabun and VX has shown that there is a very large enantioselectivity for cholinesterase inhibition k, ratios 10 -l 0 ) between the P(-) and P(+) isomers of sarin and soman, shown in Table 12. 

Addition of methyl groups to either one or both of the ethylene carbons results in chiral molecules. Muscarinic receptors (see below) display stereoselectivity for the enantiomers of methacholine. The S-(+)-enantiomer is equipotent with acetylcholine, and the R-(-)-enantiomer is approximately 20-fold less potent. Acetylcholinesterase hydrolyzes the S-(+)-isomer much slower (approximately half the rate) than acetylcholine. The R-(-)-isomer is not hydrolyzed by AChE and even acts as a weak competitive inhibitor of the enzyme. This stability toward AChE hydrolysis as well as the AChE inhibitory effect of the R-(-)-enantiomer may explain why racemic methacholine produces a longer duration of action than acetylcholine. The nicotinic receptor and AChE exhibit little stereoselectivity for the optical isomers of acetyl-a-methylcholine. 

Donepezil is another "nonclassic," centrally acting, reversible, noncompetitive AChEI that was approved in 1997 for treatment of mild-to-moderate AD and dementia. Its selectivity for AChE is 570- to 1,250-fold that for butyrylcholinesterase, and it also exhibits greater affinity for brain AChE than for AChE in the periphery (47). When compared to tacrine, donepezil exhibits greater CNS AChE selectivity, longer elimination half-life (70-104 hours in subjects older than 55 years) and little or no potential for hepatotoxicity. Donepezil is metabolized by CYP2D6 and CYP3A4 via demethylation, debenzylation, hydroxylation, oxidation to the c/s-N-oxide, and glucuronidation. The 6-0-desmethyl metabolite accounts for 11 % of a dose, and it exhibits AChE inhibitory activity comparable to that of the parent compound. 

Among the alkaloids in Lycopodium plants, huperzine A (2) was isolated from Lycopodium serratum Thunb. in 1986 and has been shown to have acetylcholine esterase (AChE) inhibitory activity and to improve memory disorders in Alzheimer s disease [13-15]. In addition to these unique activities, it was recently reported that some Lycopodium alkaloids possessing skeletons different from that of huperzine A (2) are able to enhance nerve growth factor (NFG) mRNA expression and production in human glial cells [16, 17]. Because of their useful biological activities, Lycopodium alkaloids are an attractive target in natural product chemistry, synthetic chemistry, and medicinal chemistry. 

The structure of the new alkaloid 27, named lycoposeiramine-C [25], was deduced to be a fawcettimine-t3q3e alkaloid possessing a double bond at the C-6 and C-7 positions of fawcettimine (11), and was finally established by X-ray crystallographic analysis (Fig. 2). Although our preliminary biological screening indicated that 27 possesses potent AChE inhibitory activity, further examination of the activity has been restricted by its limited availability in nature. In order to develop an efficient synthetic route to 27 for further examination, we planned the asymmetric total synthesis of 27. 

The lack of AChE inhibitory activity of lycoramine (84) and epinorlicoramine (86) could be due to the occurrence of a double bond in ring C, which does not allow these alkaloids to have the same spatial configuration as the active alkaloids of this series (93). 

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