HEPTYLENE-LINKED bis-(9-amino-1,2,3,4-tetrahydroacridine) (bis(7)-tacrine)
is a potential palliative therapeutic agent for Alzheimer's disease (AD), o
n the basis of its superior acetylcholinesterase (AChE) inhibition and memo
ry-enhancing potency relative to tacrine. In this study we report that bis(
7)-tacrine exhibits a potentially complementary central nervous system acti
on, antagonism of GABA(A) receptor function. Bis(7)tacrine displaced [H-3]m
uscimol 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, respective
ly. In whole-cell patch-clamp recordings, bis(7)-tacrine inhibited GABA-ind
uced inward current with an IC50 of 5.6 mu M, and shifted the GABA concentr
ation-response curve to the right in a parallel manner. These results sugge
st that bis(7)-tacrine is a competitive antagonist of the GABA(A) receptor.
NeuroReport 10:795-800 (C) 1999 Lippincott Williams & Wilkins.