Tacrine-xanomeline and tacrine-iperoxo hybrid ligands: Synthesis and biological evaluation at acetylcholinesterase and M muscarinic acetylcholine receptors.

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2020
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Abstract
We synthesized a set of new hybrid derivatives (7-C8, 7-C10, 7-C12 and 8-C8, 8-C10, 8-C12), in which a polymethylene spacer chain of variable length connected the pharmacophoric moiety of xanomeline, an M/M-preferring orthosteric muscarinic agonist, with that of tacrine, a well-known acetylcholinesterase (AChE) inhibitor able to allosterically modulate muscarinic acetylcholine receptors (mAChRs). When tested in vitro in a colorimetric assay for their ability to inhibit AChE, the new compounds showed higher or similar potency compared to that of tacrine. Docking analyses were performed on the most potent inhibitors in the series (8-C8, 8-C10, 8-C12) to rationalize their experimental inhibitory power against AChE. Next, we evaluated the signaling cascade at M mAChRs by exploring the interaction of Gα-PLC-β3 proteins through split luciferase assays and the myo-Inositol 1 phosphate (IP1) accumulation in cells. The results were compared with those obtained on the known derivatives 6-C7 and 6-C10, two quite potent AChE inhibitors in which tacrine is linked to iperoxo, an exceptionally potent muscarinic orthosteric activator. Interestingly, we found that 6-C7 and 6-C10 behaved as partial agonists of the M mAChR, at variance with hybrids 7-Cn and 8-Cn containing xanomeline as the orthosteric molecular fragment, which were all unable to activate the receptor subtype response.
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maspero2020tacrinexanomelinebioorganic Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Maspero, Marco;Volpato, Daniela;Cirillo, Davide;Yuan Chen, Natalia;Messerer, Regina;Sotriffer, Christoph;De Amici, Marco;Holzgrabe, Ulrike;Dallanoce, Clelia;
Journal Bioorganic chemistry
Year 2020
DOI
S0045-2068(19)31569-X
URL
Keywords
allosteric modulation bitopic ligands ellman’s assay inositol monophosphate iperoxo m(1) muscarinic acetylcholine receptor multitarget compounds phospholipase c tacrine xanomeline

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