First Gallamine-Tacrine Hybrid: Design and Characterization at Cholinesterases and the M2 Muscarinic Receptor

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• 作者：Paul W. Elsinghorst ; Julia S. Cieslik ; Klaus Mohr ; Christian Tr&auml ; nkle ; Michael Gü ; tschow
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 15, 2007
• 年：2007
• 卷：50
• 期：23
• 页码：5685 - 5695
• 全文大小：364K
• 年卷期：v.50,no.23(November 15, 2007)
• ISSN：1520-4804

文摘

Gallamine and tacrine are allosteric antagonists at muscarinic M₂ acetylcholine receptors and inhibitors ofacetylcholinesterase. At both acetylcholine-binding proteins, gallamine and tacrine are known to occupytwo different binding sites: in M₂ receptors within the allosteric binding area and in acetylcholinesterase atits catalytic and its peripheral site. To find new ligands of both targets, we designed a gallamine-tacrinedimer and several derived hybrid compounds to address the two binding sites. Their M₂ receptor allostericand acetylcholinesterase inhibitory potential was determined. The hybrid compounds revealed an allostericpotency in the low nanomolar range exceeding the allosteric potency of gallamine and tacrine by factors of100 and 4800, respectively. Cholinesterase inhibition was augmented by hybrid formation, and all compoundsexhibited IC₅₀ values in the lower nanomolar range. Thus, gallamine-tacrine hybrid formation is a valuableapproach toward high affinity ligands concurrently targeting these acetylcholine-binding proteins.