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Potential neurotoxicity of a novel aminoacridine analogueCellTox Centre, Division of Biosciences, University of Hertfordshire
Division of Psychology, University of Hertfordshire
Division of Chemical Sciences, University of Hertfordshire, Hatfield Campus, College Lane, Hatfield, Herts, AL10 9AB, UK
CellTox Centre, Division of Biosciences, University of Hertfordshire 1 A class of compounds, 9-aminoacridines, have long been known to be reversible inhibitors of acetyl cholinesterase (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 µM +/- 1.14 s.e.m., Neutral Red Uptake IC50 9.53 µM +/- 0.98 s.e.m., MTT Reduction IC80 14.6 µM +/- 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 neuro toxic property for the novel compound 2tBuTHA, a close structural analogue of Tacrine.
Key Words: acetylcholinesterase • aminoacridines • Tacrine • neuroblastoma • neurotoxicity
Human & Experimental Toxicology, Vol. 14, No. 6,
469-474 (1995) This article has been cited by other articles:
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