Bis(7)-tacrine, a novel dimeric AChE inhibitor, is a potent GABAA receptor antagonist

HEPTYLENE-LINKED bis-(9-amino-1,2,3,4-tetrahydroacridine) (bis(7)-tacrine) is a potential palliative therapeutic agent for Alzheimer's disease (AD), on the basis of its superior acetylcholinesterase (AChE) inhibition and memory-enhancing potency relative to tacrine. In this study we report that bis(7)-tacrine exhibits a potentially complementary central nervous system action, antagonism of GABA(A) receptor function. Bis(7)tacrine displaced [H-3]muscimol from rat brain membranes with an apparent K-i of 6.0 mu M; tacrine and physostigmine were shown to be 18 and 170 times less potent, respectively. In whole-cell patch-clamp recordings, bis(7)-tacrine inhibited GABA-induced inward current with an IC50 of 5.6 mu M, and shifted the GABA concentration-response curve to the right in a parallel manner. These results suggest that bis(7)-tacrine is a competitive antagonist of the GABA(A) receptor. NeuroReport 10:795-800 (C) 1999 Lippincott Williams & Wilkins.