Inhibitor Report for: DTE-bis8-Tacrine

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 cholinesterase inhibitors were obtained from cis-1,2-alpha-dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target compounds are potent acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors in the nanomolar concentration range. Compound 11b bearing an octylene linker exhibited interactions with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Yet upon irradiation with light, the mechanism of interaction varied from one photochromic form to another, which was investigated by kinetic studies and proved "photoswitchable". The AChE-induced beta-amyloid (Abeta) aggregation assay gave further experimental support to this finding: Abeta1-40 aggregation catalyzed by the PAS of AChE might be inhibited by compound 11b in a concentration-dependent manner and seems to occur only with one photochromic form. Computational docking studies provided potential binding modes of the compound. Docking studies and molecular dynamics (MD) simulations for the ring-open and -closed form indicate a difference in binding. Although both forms can interact with the PAS, more stable interactions are observed for the ring-open form based upon stabilization of a water molecule network within the enzyme, whereas the ring-closed form lacks the required conformational flexibility for an analogous binding mode. The photoswitchable inhibitor identified might serve as valuable molecular tool to investigate the different biological properties of AChE as well as its role in pathogenesis of AD in in vitro assays.