Inhibitors of acetylcholinesterase from plants

Natural products are already described as promising pool for the discovery of acetylcholinesterase (AChE) inhibitory agents, e.g. galantamine, which are used as standard therapeutics in Alzheimers disease. For the efficient discovery of plant constituents with improved bioavailability and anticholinesterase activity two strategies are followed up, i) the computer-aided drug discovery and ii) a random screening by means of a bioautographic thin layer chromatography test. The computer-aided drug discovery allows virtual screening of 3D databases consisting of natural constituents. These are screened against a pharmacophore model generated from the AChE crystal structure co-crystallized with galanthamine. Random search of secondary plant metabolites for AChE inhibitory activity is performed by a bioautographic thin layer chromatographic test using Ellmans reagent. Promising plant crude extracts are enriched in bioguided manner focusing on the isolation plant constituent/s with reliable potency to inhibit AChE . For both approaches an in vitro enzyme assay for the quantitative determination of the AChE inhibitory activity as well as in vivo release of acetylcholine in the nucleus accumbens of rat brain are conducted. Facilitatory and receptor-releated effects on neurotransmission are revealed by the influence of substances on stimulation-induced release in vivo and on release of neurotransmitters from synaptosomes. Effects on nicotinic-cholinergic transmission are investigated by an international co-operator. These results are accomplished by behaviour tests to evaluate memory enhancement in mice. Four plants will be investigated in the course of this project: Leontopodium alpinum, Scopolia carniolica, Cichorium intybus und Magnolia soulangiana. Preliminary pharmacological test results obtained with extracts and enriched fractions indicate the presence of AChE inhibitory secondary metabolites of the above mentioned plant taxa.

Natural products are already described as promising pool for the discovery of acetylcholinesterase (AChE) inhibitory agents, e.g. galantamine, which are used as standard therapeutics in Alzheimer`s disease. For the efficient discovery of plant constituents with improved bioavailability and anticholinesterase activity two strategies are followed up, i) the computer-aided drug discovery and ii) a random screening by means of a bioautographic thin layer chromatography test. The computer-aided drug discovery allows virtual screening of 3D databases consisting of natural constituents. These are screened against a pharmacophore model generated from the AChE crystal structure co-crystallized with galanthamine. Random search of secondary plant metabolites for AChE inhibitory activity is performed by a bioautographic thin layer chromatographic test using Ellman`s reagent. Promising plant crude extracts are enriched in bioguided manner focusing on the isolation plant constituent/s with reliable potency to inhibit AChE . For both approaches an in vitro enzyme assay for the quantitative determination of the AChE inhibitory activity as well as in vivo release of acetylcholine in the nucleus accumbens of rat brain are conducted. Facilitatory and receptor-releated effects on neurotransmission are revealed by the influence of substances on stimulation-induced release in vivo and on release of neurotransmitters from synaptosomes. Effects on nicotinic-cholinergic transmission are investigated by an international co-operator. These results are accomplished by behaviour tests to evaluate memory enhancement in mice. Four plants will be investigated in the course of this project: Leontopodium alpinum, Scopolia carniolica, Cichorium intybus und Magnolia soulangiana. Preliminary pharmacological test results obtained with extracts and enriched fractions indicate the presence of AChE inhibitory secondary metabolites of the above mentioned plant taxa.