title: Optical control of acetylcholinesterase with a tacrine switch.
abstract: Photochromic ligands have been used to control a variety of biological functions, especially in neural systems. Recently, much effort has been invested in the photocontrol of ion channels and G-protein coupled receptors found in the synapse. Herein, we describe the expansion of our photopharmacological approach toward the remote control of an enzyme. Building on hallmark studies dating from the late 1960s, we evaluated photochromic inhibitors of one of the most important enzymes in synaptic transmission, acetylcholinesterase (AChE). Using structure-based design, we synthesized several azobenzene analogues of the well-known AChE inhibitor tacrine (THA) and determined their effects on enzymatic activity. One of our compounds, AzoTHA, is a reversible photochromic blocker of AChE in vitro and ex vivo with high affinity and fast kinetics. As such, AzoTHA can be used to control synaptic transmission on the neuromuscular endplate based on the light-dependent clearance of a neurotransmitter.
authors.affiliation: Department Chemie, Ludwig-Maximilians-Universität München und Center of Integrated Protein Science Munich, Butenandtstrasse 5-13, 81377 München (Germany).
authors.forename: Johannes
authors.initials: J
authors.lastname: Broichhagen
authors.forename: Innokentij
authors.initials: I
authors.lastname: Jurastow
authors.forename: Katharina
authors.initials: K
authors.lastname: Iwan
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kummer
authors.forename: Dirk
authors.initials: D
authors.lastname: Trauner
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D013619:Tacrine / Q000737:chemistry*
chemical_list: D013619:Tacrine; D000110:Acetylcholinesterase
keywords: acetylcholinesterase; photochromic blockers; photopharmacology; tacrine; tracheal tensometry