Collection of Czechoslovak Chemical Communications - digital archive 

Abstract

The kinetics was studied of the inhibition of solubilized rat brain acetylcholinesterase by 9-hydrazino-1,2,3,4-terahydroacridine (THH) and 9-amino-10-methyl-1,2,3,4-tetrahydroacridinium (QTHA); the inhibitory effect was compared with the effect of tacrine (9-amino-1,2,3,4-tetrahydroacridine, THA). It was observed that THH is a reversible, noncompetitive inhibitor of rat brain acetylcholinesterase (K_i = 0.16 μM) and that it binds, similarly to THA, to the hydrophobic domain of the active center of acetylcholinesterase thus simultaneously inhibiting the formation of complex ES₂ with acetylcholine as substrate. This eliminates the inhibition of acetylcholinesterase by an excess of substrate. QTHA is a mixed, competitive-non-competitive inhibitor characterized by K_{I comp} = 5.3 μM and K_{i noncomp} = 0.08 μM. QTHA binds to an entirely different site of the active surface of acetylcholinesterase than THA and THH. This binding site is most likely the so-called β-anionic or also peripheric anionic site to which, e.g. atropine is also bound. Both inhibitors studied form with acetylcholinesterase a reversible, enzymatically inactive complex in which one inhibitor molecule is bonded to each active center of the enzyme.