A Hydrazide Linker Strategy for Heterobivalent Compounds as Ortho- and Allosteric Ligands of Acetylcholine-Binding Proteins

Author(s): Paul W. Elsinghorst, Wolfgang Hartig, Daniela Gundisch, Klaus Mohr, Christian Trankle, Michael Gutschow

Journal Name: Current Topics in Medicinal Chemistry

Volume 11 , Issue 22 , 2011

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The occurrence of orthosteric and allosteric binding sites is a characteristic common feature of several acetylcholine- binding proteins, like acetylcholinesterase or the nicotinic and muscarinic acetylcholine receptors. These proteins are involved in a number of neurological disorders, such as Alzheimers disease, and represent important therapeutic targets for the development of heterodimeric ligands addressing both of their binding sites. Among the pharmacophores, which have been combined in such heterodimers, the tetrahydroacridine derivative tacrine has attracted particular interest. This review discusses the chemistry behind the linker connection of tacrine to other pharmacophores and summarizes the types of linkers established to date. Especially, the development of a hydrazide linker for tacrine-derived heterodimers is highlighted by applications in the inhibition of cholinesterases, the bivalent binding to nicotinic and muscarinic acetylcholine receptors, as well as the histochemical imaging of acetylcholinesterase and amyloid-β.

Keywords: Acetylcholinesterase, allosteric/orthosteric ligands, amyloid-β, bivalent ligands, butyrylcholinesterase, heterodimers, hydrazides, linker, muscarinic acetylcholine receptors, nicotinic acetylcholine receptors, Cholinergic transmission, cholinergic synapses, hydrolyticdeacylation, synthetic inhibitors, neurofibrillary tangles

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Article Details

Year: 2011
Page: [2731 - 2748]
Pages: 18
DOI: 10.2174/156802611798184427
Price: $65

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