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

Article abstract of DOI:10.1021/jm070859s

Gallamine and tacrine are allosteric antagonists at muscarinic M ₂ 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.