First gallamine-tacrine hybrid: design and characterization at cholinesterases and the M2 muscarinic receptor.

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Elsinghorst PW, Cieslik JS, Mohr K, Trankle C, Gutschow M

First gallamine-tacrine hybrid: design and characterization at cholinesterases and the M2 muscarinic receptor.

J Med Chem. 2007 Nov 15;50(23):5685-95. Epub 2007 Oct 18.

PubMed ID

17944454 [ View in PubMed

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Abstract

Gallamine and tacrine are allosteric antagonists at muscarinic M2 acetylcholine receptors and inhibitors of acetylcholinesterase. At both acetylcholine-binding proteins, gallamine and tacrine are known to occupy two different binding sites: in M2 receptors within the allosteric binding area and in acetylcholinesterase at its catalytic and its peripheral site. To find new ligands of both targets, we designed a gallamine-tacrine dimer and several derived hybrid compounds to address the two binding sites. Their M2 receptor allosteric and acetylcholinesterase inhibitory potential was determined. The hybrid compounds revealed an allosteric potency in the low nanomolar range exceeding the allosteric potency of gallamine and tacrine by factors of 100 and 4800, respectively. Cholinesterase inhibition was augmented by hybrid formation, and all compounds exhibited IC50 values in the lower nanomolar range. Thus, gallamine-tacrine hybrid formation is a valuable approach toward high affinity ligands concurrently targeting these acetylcholine-binding proteins.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Gallamine triethiodide	Acetylcholinesterase	Protein	Humans	Yes	Inhibitor	Details
Gallamine triethiodide	Muscarinic acetylcholine receptor M2	Protein	Humans	Yes	Antagonist	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Tacrine	Acetylcholinesterase	IC 50 (nM)	926	N/A	N/A	Details