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Title: An investigation into the neuropharmacology and toxicology of some novel analogues of Tacrine.
Author: Walker, Tracy Michelle.
Awarding Body: University of Herfordshire
Current Institution: University of Hertfordshire
Date of Award: 1995
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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 (AChE). 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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacology & pharmacy & pharmaceutical chemistry Pharmacology Biochemistry