131986-45-3Relevant articles and documents
Tacrine-xanomeline and tacrine-iperoxo hybrid ligands: Synthesis and biological evaluation at acetylcholinesterase and M1 muscarinic acetylcholine receptors
Cirillo, Davide,Dallanoce, Clelia,De Amici, Marco,Holzgrabe, Ulrike,Maspero, Marco,Messerer, Regina,Sotriffer, Christoph,Volpato, Daniela,Yuan Chen, Natalia
, (2020/02/11)
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 M1/M4-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 M1 mAChRs by exploring the interaction of Gαq-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 M1 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.
Synthesis and evaluation of xanomeline analogs-Probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor
Kane, Brian E.,Grant, Marianne K.O.,El-Fakahany, Esam E.,Ferguson, David M.
, p. 1376 - 1392 (2008/09/18)
A series of xanomeline analogs were synthesized and evaluated for binding at the M1 muscarinic acetylcholine receptor (M1 receptor). Specifically, compounds that substitute the O-hexyl chain of xanomeline with polar, ionizable, or conformationally restricted moieties were assessed for their ability to bind to the M1 receptor in a wash-resistant manner (persistent binding). From our screen, several novel ligands that persistently bind to the M1 receptor with greater affinity than xanomeline were discovered. Results indicate that persistent binding may arise not only from hydrophobic interactions but also from ionic interactions with a secondary M1 receptor binding site. Herein, a qualitative model that accounts for both binding scenarios is proposed and applied to understand the structural basis to wash-resistant binding and long-acting effects of xanomeline-based compounds.
Identification of side chains on 1,2,5-thiadiazole-azacycles optimal for muscarinic m1 receptor activation
Sauerberg, Per,Jeppesen, Lone,Olesen, Preben H.,Sheardown, Malcolm J.,Fink-Jensen, Anders,Rasmussen, Thoger,Rimvall, Karin,Shannon, Harlan E.,Bymaster, Frank P.,DeLapp, Neil W.,Calligaro, Dave O.,Ward, John S.,Whitesitt, Celia A.,Thomsen, Christian
, p. 2897 - 2902 (2007/10/03)
Series of analogs to the functional m1 selective agonist, xanomeline (hexyloxy-TZTP), were evaluated for their in vitro ml efficacy in cell lines transfected with the human m1 receptor. Systematic variation of the side chain and the azacyclic ring led to the discovery of potent muscarinic agonists with robust m1 efficacy, all having the phenylpropargyloxy/thio as the side chain. The most selective compound was the phenylpropargylthio- [3.2.1] endo analog 28, which is a potent and efficacious m1 agonist with no m2 activity.
