Potential neurotoxicity of a novel aminoacridine analogue.
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.
Walker
T M
TM
CellTox Centre, University of Hertfordshire, Hatfield, Herts, UK.
Starr
B
B
Dewhurst
B B
BB
Atterwill
C
C
D000609:Aminoacridines / Q000138:chemical synthesis / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000633:toxicity*; D005106:Exploratory Behavior / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology; D009498:Neurotoxins / Q000138:chemical synthesis / Q000633:toxicity*; D009499:Neutral Red / Q000378:metabolism; D010084:Oxidation-Reduction; D012601:Scopolamine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D014407:Tumor Cells, Cultured
C097023:2-tert-butyl-9-amino-1,2,3,4-tetrahydroacridine; D000609:Aminoacridines; D002800:Cholinesterase Inhibitors; D009498:Neurotoxins; D009499:Neutral Red; D013619:Tacrine; D008668:Metallothionein; D012601:Scopolamine