von Christian PilgerPaderborn, Univ.-GH, Diss., 200

Pilger, Christian

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Galanthamin als AChE-Inhibitor – Beiträge zum rationalen Wirkstoffdesignby Christian PilgerAlzheimer's dementia (AD) is characterized by a progressive memory loss, that leads toprofound emotional disturbances in later stages. The disease is accompanied by dysfunctionswithin the system of cholinergic neurotransmission in the centralnervous system. The nerve impuls in cholinergic synapses is terminatedby the enzyme acetylcholinesterase (AChE), which cleaves theneurotransmitter acetylcholine. Reversible inhibition of this enzymeleads to an increase of the neurotransmitter concentration within thesynaptic cleft, which positively affects patients suffering from AD.Based on the cholinergic hypothesis, this treatment solely has lead to drugs for the symptomatictreatment of AD.Being a potent inhibitor of AChE with an acceptable pharmacological and toxicological profile,the amaryllidaceae alkaloid (–)-galanthamine is a promising lead structure for the developmentof the next generation AD drugs.In the course of this dissertation a new synthetic strategy for galanthamine was developed, whichis based on a stereoselective Heck reaction as the key step. The approach lead to the tetracyclicframework of the galanthamine moiety. The new pathway was found to be a versatile tool for thesynthesis of derivatives of the lead structure galanthamine.In accompanying Molecular Modelling studies the interactions between the enzyme and eachmember of a database of known galanthamine derivatives was investigated by automateddocking. The employed techniques allowed for the correct prediction of the structure of thegalanthamine/AChE complex (species: Torpedo californica). Based on the docking results a 3D-QSAR model was developed and successfully validated by different statistical methods. Thismodel is a useful tool to estimate the biological activities of new galanthamine deivatives.OONOH(–)-galanthamine

Galanthamin als AChE-Inhibitor : Beiträge zum rationalen Wirkstoffdesign

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