An investigation into the neuropharmacology and toxicology of some novel analogues of Tacrine.
A series of novel 9-amino-1,2,3,4-tetrahydroacridine compounds with alkyl
substituents in the saturated ring were synthesized. The selected lead compound
was 2-t-butyl-9-amino- 1,2,3,4-tetrahydroacridine (2tBuTHA), which in
preliminary studies demonstrated a potent inhibition of acetylcholinesterase
In vitro cytotoxicity profiles of the analogues in comparison to the unsubstituted
parent compound, Tacrine, were examined in three cell types with differing basal
proliferation and drug metabolizing characteristics. 2tBuTHA was shown to be a
potent cytotoxin with IC50 values in a low micromolar range, in contrast to
Tacrine which only elicited cytotoxicity at approximately ten fold higher
concentrations. The neuronal cell type appeared to be slightly more sensitive to
2tBuTHA cytotoxicity than either the fibroblast or hepatocyte cultures, suggesting
2tBuTHA may have a selective neurotoxic potential.
The effects of 2tBuTHA administration were studied in cognitive behavioural
paradigms capable of detecting improvements and impairments in working
memory. 2tBuTHA was shown to cause short lasting, detrimental effects on
working memory which resembled scopolamine induced impairments, in contrast
to Tacrine which partially ameliorated a scopolamine induced effect. 2tBuTHA
was also found to be more potent at displacing muscarinic acetylcholine receptor
(mAChR) antagonists than inhibiting AChE. Thus, the acute effects of 2tBuTHA
on working memory were interpreted to result from central mAChR blockade.
A catalepsyp aradigmw as usedt o study potential in vivo antimuscarinice ffects in
the striatum following 2tBuTHA administration. Pre-treatment with 2tBuTHA
resultedi n a decreasein haloperidol inducedc atalepsy. As a result of the long
delay between treatment and the measurement of catalepsy, the effect was
considered unlikely to result from mAChR antagonism, and further indicated a
possible neurotoxic effect of 2tBuTHA resulting in a loss of cholinergic
interneuronsin the striatum.
It is proposedt hat 2tBuTHA has a two phasem echanismo f neurotoxic action, the
acute effects arising from central mAChR blockade followed by a delayed effect,
the mechanism(so) f which is unknown but which may result from a prolonged
disturbance of normal neuronal function. Along with the known actions of
2tBuTHA, and based on the structural similarity to Tacrine with its range of
neuropharmacological properties, several possible sites/effects where by 2tBuTHA
might result in CNS neurotoxicity are discussed.