Structural analogs of hemicholinium: effects on cholinergic and GABAergic markers in the CNS.
The synthesis and neurotoxic effects of several structural analogs of hemicholinium were studied. All compounds were injected unilaterally into the lateral ventricle (4 nmol) and the effects of the hemicholinium derivatives on choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) activity were compared with those of AF64A in an equimolar concentration. Structures of the newly synthesized compounds were confirmed by i.r., NMR and u.v. spectrometry and elemental analysis. The most specific cholinotoxic effects were observed with a,a-bis[di(2-chloroethyl)amino]4,4-biacetophenone (toxin 7). This compound causes specific decrease of ChAT activity in the brain structures (hippocampus and cortex) containing cholinergic terminals deriving from septum and the nucleus basalis magnocellularis (NBM), respectively. Large ChAT-positive magnocellular neurons in the NBM became paler and lost their processes following treatment with toxin 7 after 1 week.
Maysinger
D
D
Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
Zorc
B
B
Leavitt
B R
BR
Butula
I
I
Chubb
F L
FL
Cuello
A C
AC