Tetrahydroaminoacridine (THA) has been reported to improve the memory of persons with Alzheimer's disease, but its mechanism of action is uncertain. We found that clinically effective concentrations, 0.03-0.3 microM, readily inhibit acetylcholinesterase and butyrylcholinesterase from rabbit hippocampal tissue in artificial cerebrospinal fluid (CSF) at 37 degrees C with physiological levels of substrate Above 1 microM, THA was found to act at primary and allosteric sites on M1 and M2 muscarine receptors as an antagonist. This is not clinically important, and low levels of THA do not improve the binding of the agonist, oxotremorine-M. Only 10-1000 microM THA has been shown to block K+ channels. Thus THA probably acts as an esterase inhibitor.