A hydrazide linker strategy for heterobivalent compounds as ortho- and allosteric ligands of acetylcholine-binding proteins

• Published in: Current topics in medicinal chemistry Vol. 11; no. 22; p. 2731
• Main Authors: Elsinghorst, Paul W, Härtig, Wolfgang, Gündisch, Daniela, Mohr, Klaus, Tränkle, Christian, Gütschow, Michael
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.11.2011
• Subjects: Acetylcholinesterase - metabolism; Allosteric Site - drug effects; Animals; Humans; Hydrazines - chemistry; Ligands; Nervous System Diseases - drug therapy; Nervous System Diseases - metabolism; Receptors, Muscarinic - metabolism; Receptors, Nicotinic - metabolism; Structure-Activity Relationship
• ISSN: 1873-4294
• DOI: 10.2174/156802611798184427

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 Alzheimer's 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.