- Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor
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A novel series of 30 symmetric bispyridinium and related N-heteroaromatic bisquaternary salts with a propane-1,3-diyl linker was synthesized and characterized for their binding affinity at the MB327 binding site of nicotinic acetylcholine receptor (nAChR) from Torpedo californica. Compounds targeting this binding site are of particular interest for research into new antidotes against organophosphate poisoning, as therapeutically active 4-tert-butyl-substituted bispyridinium salt MB327 was previously identified as a nAChR re-sensitizer. Efficient access to the target compounds was provided by newly developed methods enabling N-alkylation of sterically hindered or electronically deactivated heterocycles exhibiting a wide variety of functional groups. Determination of binding affinities toward the MB327 binding site at the nAChR, using a recently developed mass spectrometry (MS)-based Binding Assay, revealed that several compounds reached affinities similar to that of MB327 (pKi=4.73±0.03). Notably, the newly prepared lipophilic 4-tert-butyl-3-phenyl-substituted bispyridinium salt PTM0022 (3 h) was found to have significantly higher binding affinity, with a pKi value of 5.16±0.07, thus representing considerable progress toward the development of more potent nAChR re-sensitizers.
- Rappenglück, Sebastian,Sichler, Sonja,H?fner, Georg,Wein, Thomas,Niessen, Karin V.,Seeger, Thomas,Paintner, Franz F.,Worek, Franz,Thiermann, Horst,Wanner, Klaus T.
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- Gold-catalyzed diastereoselective cycloisomerization of alkylidene-cyclopropane-bearing 1,6-diynes
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An unprecedented gold-catalyzed diastereoselective cycloisomerization of 1,6-diynes bearing an alkylidene cyclopropane moiety has been developed. This methodology enables rapid access to a variety of 1,2-trimethylenenorbornanes, which are important building blocks in the preparations of abiotic and sesquiterpene core structures. When gold met alkylidenecyclopropane: Cationic gold catalysts can mediate the highly exothermic (≈60 kcal mol-1) cycloisomerization of 1,6-diynes bearing an alkylidene cyclopropane moiety. This diastereoselective methodology efficiently generates 1,2- trimethylenenorbornanes, an important building block for abiotic targets and sesquiterpene natural products. DCE=1,2-dichloroethane, Tf= trifluoromethanesulfonyl, Tol=Tolyl.
- Zheng, Hongchao,Adduci, Laura L.,Felix, Ryan J.,Gagne, Michel R.
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supporting information
p. 7904 - 7907
(2014/08/05)
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- BICYCLIC AZA COMPOUNDS AS MUSCARINIC M1 RECEPTOR AGONISTS
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This invention relates to compounds (Formula (1)) that are agonists of the muscarinic M1 receptor and which are useful in the treatment of muscarinic M1 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and
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Page/Page column 57; 58
(2014/04/04)
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- Structure-property correlations in model compounds of oligomer liquid crystals
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Structure-property correlations of the following model compounds for oligomer liquid crystals (LCs) have been investigated: monomers, C 6H5O(CH2)xCH3 (x = 4 and 5); dimers, C6H5O
- Sasanuma, Yuji,Ono, Tetsushi,Kuroda, Yoshihiko,Miyazaki, Emi,Hikino, Ken,Arou, Jun,Nakata, Kohji,Inaba, Hideaki,Tozaki, Ken-Ichi,Hayashi, Hideko,Yamaguchi, Kentaro
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p. 13163 - 13176
(2007/10/03)
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