Poly(ethylene glycol) as a scaffold for high-affinity open-channel blockers of the mouse nicotinic acetylcholine receptor.
High-affinity blockers for an ion channel often have complex molecular structures that are synthetically challenging and/or laborious. Here we show that high-affinity blockers for the mouse nicotinic acetylcholine receptor (AChR) can be prepared from a structurally simple material, poly(ethylene glycol) (PEG). The PEG-based blockers (PQ1-5), comprised of a flexible octa(ethylene glycol) scaffold and two terminal quaternary ammonium groups, exert low- to sub-micromolar affinities for the open AChR pore (measured via single-channel analysis of AChRs expressed in human embryonic kidney cells). PQ1-5 are comparable in pore-binding affinity to the strongest AChR open-channel blockers previously reported, which have complex molecular structures. These results suggest a general approach for designing potent open-channel blockers from a structurally flexible polymer. This design strategy involves simple synthetic procedures and does not require detailed information about the structure of an ion-channel pore.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Wan-Chen
WC
Lin
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Stuart
S
Licht
D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D018733:Nicotinic Antagonists / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011978:Receptors, Nicotinic / Q000378:metabolism*
D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D011092:Polyethylene Glycols