m-(N,N,N-Trimethylammonio)trifluoroacetophenone: a femtomolar inhibitor of acetylcholinesterase

m-(N,N,N-Trimethylammonio)trifluoroacetophenone is a potent, reversible, time-dependent inhibitor of acetylcholinesterases. The respective second-order rate constants (k sub(on)) for binding of the ketone to enzymes from Electrophorus electricus and Torpedo californica are (1.2 plus or minus 0.2) x 10 super(5) and (1.0 + 0.2) x 10 super(5) M super(-1) s super(-1), while the corresponding dissociation rate constants (k sub(off)) are (1.0 plus or minus 0.2) x 10 super(-5) and (1.0 plus or minus 0.3) x 10 super(-4) s super(-1). Therefore, the apparent dissociation constants of the enzyme-inhibitor complexes K sub(i) super(app) = k sub(off)/k sub(on)) are 80 plus or minus 20 pM and 1.0 plus or minus 0.3 nM, respectively. Because the free ketone is the form that inhibits acetylcholinesterases, intrinsic dissociation constants were calculated by correcting the K sub(i) super(app) values for the extent of hydration of the inhibitor. The resulting K sub(i) values are 1.3 and 15 fM for inhibitions of E. electricus and T. californica acetylcholinesterases, respectively.