Bis(7)-tacrine, a novel dimeric AChE inhibitor, is a potent GABA(A) 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 [3H]muscimol from rat brain membranes with an apparent Ki of 6.0 microM; 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 microM, 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.
Li
C Y
CY
Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Wang
H
H
Xue
H
H
Carlier
P R
PR
Hui
K M
KM
Pang
Y P
YP
Li
Z W
ZW
Han
Y F
YF
D000544:Alzheimer Disease / Q000201:enzymology*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004558:Electric Stimulation; D004594:Electrophysiology; D058787:GABA-A Receptor Antagonists; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010830:Physostigmine / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D058787:GABA-A Receptor Antagonists; D011976:Receptors, Muscarinic; D013619:Tacrine; D005680:gamma-Aminobutyric Acid; D010830:Physostigmine