Abstract
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
Current Topics in Medicinal Chemistry
Title: A Hydrazide Linker Strategy for Heterobivalent Compounds as Ortho- and Allosteric Ligands of Acetylcholine-Binding Proteins
Volume: 11 Issue: 22
Author(s): Paul W. Elsinghorst, Wolfgang Hartig, Daniela Gundisch, Klaus Mohr, Christian Trankle and Michael Gutschow
Affiliation:
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
Abstract: 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.
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Cite this article as:
W. Elsinghorst Paul, Hartig Wolfgang, Gundisch Daniela, Mohr Klaus, Trankle Christian and Gutschow Michael, A Hydrazide Linker Strategy for Heterobivalent Compounds as Ortho- and Allosteric Ligands of Acetylcholine-Binding Proteins, Current Topics in Medicinal Chemistry 2011; 11 (22) . https://dx.doi.org/10.2174/156802611798184427
DOI https://dx.doi.org/10.2174/156802611798184427 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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