HIGH-AFFINITY [3H]THA (TETRAHYDROAMINOACRIDINE) BINDING-SITES IN RAT-BRAIN

Tetrahydroaminoacridine (THA), an acetylcholinesterase inhibitor that is reported to have significant effects on cognition and memory in Alzheimer's disease patients, binds to rat brain membranes in a saturable and reversible manner. Computer analysis of the binding data revealed high- and low-affinity sites with K(d) values of 97.8 nM and 4.65 mu-M and B(max) values of 4.13 and 114 pmol/mg protein. Autoradiographic studies show that these binding sites are not colocalized with acetylcholinesterase activity. The binding of [H-3]THA to membranes does not appear to be related to receptors for several neurotransmitters/neuromodulators, including acetylcholine and other acetylcholinesterase inhibitors. Amiridin, a closely related acetylcholinesterase inhibitor, was able to block specific [H-3]THA binding (IC50 = 1.05-mu-M). While the function of THA mediated by these sites is unknown, they may be responsible in part for the distinct clinical effects of tetrahydroaminoacridine compared to other acetylcholinesterase inhibitors.