title: Polymer-based open-channel blockers for the acetylcholine receptor: the effect of spacer length on blockade kinetics.
abstract: Blocking open ion channels provides a promising way to modulate synaptic transmission. Using the muscle-type acetylcholine receptor (AChR) as a test system, we seek to develop blockers that have blockade kinetics tunable via structural modifications. Here we investigate whether the blockade kinetics can be modulated by specifying the length of a poly(ethylene glycol) (PEG) spacer incorporated into the blocker. Single-channel electrophysiological experiments show that simple bis(trimethylammonium) compounds ( 1a- 3) both activate the AChR and block the open channel. The blockade kinetics are found to depend on spacer length: both the association and dissociation rate constants decrease with increasing spacer length. The decrease in the association rate constant can be quantitatively explained by the entropic cost of polymer confinement in the transmembrane lumen, while the decrease in the dissociation rate constant is consistent with weak, additive noncovalent interactions between the channel and the spacer. These results provide useful insights into the future design of kinetically tunable open-channel blockers for the AChR.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Wan-Chen
authors.initials: WC
authors.lastname: Lin
authors.forename: Stuart
authors.initials: S
authors.lastname: Licht
mesh_terms: D000818:Animals; D018680:Cholinergic Antagonists / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry*; D011950:Receptors, Cholinergic / Q000737:chemistry* / Q000378:metabolism; D050337:Trimethyl Ammonium Compounds / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D018680:Cholinergic Antagonists; D011950:Receptors, Cholinergic; D050337:Trimethyl Ammonium Compounds; D011092:Polyethylene Glycols