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

Neuroreport. 1999 Mar 17;10(4):795-800. doi: 10.1097/00001756-199903170-00024.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / enzymology*
  • Animals
  • Cholinesterase Inhibitors / pharmacology*
  • Electric Stimulation
  • Electrophysiology
  • GABA-A Receptor Antagonists*
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Patch-Clamp Techniques
  • Physostigmine / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, Muscarinic / drug effects
  • Receptors, Muscarinic / metabolism
  • Tacrine / analogs & derivatives*
  • Tacrine / pharmacology*
  • gamma-Aminobutyric Acid / pharmacology

Substances

  • Cholinesterase Inhibitors
  • GABA-A Receptor Antagonists
  • Receptors, Muscarinic
  • Tacrine
  • gamma-Aminobutyric Acid
  • Physostigmine