Inhibitor Report for: AzoTHA

Considerable effort has previously been invested in a light-controlled inhibition of the enzyme acetylcholinesterase (AChE). We found that a novel azobenzene-based bistacrine AChE inhibitor switched faster than the known dithienylethene based bistacrine and inverted the photo-controlled interactions of the photoisomers compared to its dithienylethene congener. Furthermore, we have optimized a previously described light-controlled tacrine-based AChE inhibitor. Isomerization upon irradiation with UV light of the novel inhibitor was observed in aqueous medium and showed no fatigue over several cycles. The cis-enriched form showed an 8.4-fold higher inhibition of hAChE compared with its trans-enriched form and was about 30-fold more active than the reference compound tacrine with a single-digit nanomolar inhibition. We went beyond proof-of-concept to discover photoswitchable AChE inhibitors with pharmacologically desirable nanomolar inhibition, cis-on effect, and pronounces differences between the photoisomers.

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.