ABSTRACT
1. A class of compounds, 9-aminoacridines, have long been known to be reversible inhibitors of acetylcholinesterase (AChE-EC 3.1.1.7), the most familiar of which is 9-amino-1,2,3,4-tetrahydroacridine (Tacrine). 2. A novel aminoacridine was synthesised: -2-tertiary-butyl-9-amino-1,2,3,4- tetrahydroacridine (2tBuTHA). 3. In vitro comparisons of the acetylcholinesterase inhibitory potential and neurotoxicity compared to Tacrine were performed using a chemically differentiated neuroblastoma cell line (Neuro 2A). 2tBuTHA, but not Tacrine, was cytotoxic to the neural cell following 20 h exposure, despite being the least potent AChE inhibitor (IC80 AChE 12.53 microM +/- 1.14 s.e.m., Neutral Red Uptake IC50 9.53 microM +/- 0.98 s.e.m., MTT Reduction IC80 14.6 microM +/- 1.43 s.e.m.). 4. In vivo studies used a novel application of a five arm radial maze to assess neuropharmacological effects on working memory in control and Scopolamine (1 mg kg-1 i.p.) treated mice. There was an impairment of short term cognitive function with 2tBuTHA (15 mg kg-1 i.p.), but not Tacrine (10 mg kg-1 i.p.) which improved the Scopolamine deficit as expected. 5. This combined in vitro and in vivo data infers a neurotoxic property for the novel compound 2tBuTHA, a close structural analogue of Tacrine.
Subject(s)
Aminoacridines/toxicity , Cholinesterase Inhibitors/toxicity , Neurotoxins/toxicity , Tacrine/analogs & derivatives , Tacrine/toxicity , Aminoacridines/chemical synthesis , Analysis of Variance , Animals , Behavior, Animal/drug effects , Cholinesterase Inhibitors/chemical synthesis , Exploratory Behavior/drug effects , Memory/drug effects , Metallothionein/metabolism , Mice , Neuroblastoma/pathology , Neurotoxins/chemical synthesis , Neutral Red/metabolism , Oxidation-Reduction , Scopolamine/pharmacology , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/chemistry , Tumor Cells, CulturedABSTRACT
Wistar-derived rat embryos were most sensitive to maternally administered cyclophosphamide on Days 9.5 and 10.5 of gestation and to chlorambucil on Day 9.5 of gestation. The spectrum of malformations and the dose-response behavior of both drugs were similar. Chlorambucil was three times more potent than cyclophosphamide on an mg/kg basis. The drugs showed additive behavior when administered in combination. The teratogenic effects of the individual or combined drugs were reduced by protective doses of cysteine or glutathione. Studies with analogs of cyclophosphamide have suggested that the whole molecule is involved in teratogenesis.
