Abstract
1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol 2-ethylphenylcarbamate N-oxide hydrochloride (3aS-cis) (CHF2819) is a novel acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral administration in rats. In vivo studies show that CHF2819 (0.5, 1.5, and 4.5 mg/kg p.o.) significantly increases acetylcholine levels in young adult rat hippocampus in a dose-dependent manner. Moreover, aged animals, which show a significant decrease in basal acetylcholine levels with respect to young adult rats, also exhibit a marked increase in the hippocampal concentrations of this neurotransmitter after the administration of CHF2819. This compound (1.5 mg/kg p.o.) significantly attenuates scopolamine-induced amnesia in a passive avoidance task. Furthermore, CHF2819 induces a significant decrease in dopamine levels and a significant elevation of extracellular concentrations of 5-hydroxytryptamine, whereas it does not modify norepinephrine and γ-aminobutyric acid levels in the hippocampus of young adult rats. Functional observational battery screening demonstrates that CHF2819 (1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic, neuromuscular, and sensorimotor domains, as well as physiological end points (body weight and temperature). However, this compound induces involuntary motor movements (ranging from mild tremors to myoclonic jerks) in a dose-dependent manner. These findings suggest that the anti-amnestic properties of CHF2819, together with its stimulatory effect on cholinergic and serotonergic functions, might have a therapeutic potential mainly for the symptomatic treatment of Alzheimer's disease patients in which the cognitive impairment is accompanied by a depressive syndrome.
Footnotes
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Send reprint requests to: Luigia Trabace, Ph.D., Department of Pharmacology and Human Physiology, Medical School, University of Bari, Policlinico Piazza Giulio Cesare 11, 701 24 Bari, Italy. E-mail:trabace{at}farmacol.uniba.it
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↵1 This work was supported by Chiesi Farmaceutici S.p.A. and Biotechnology and Biological Sciences Research Council.
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↵2 Current address: Pharmacology Department, Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43100 Parma, Italy.
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↵3 Current address: Department of Neurobiology, The Babraham Institute, Babraham, Cambridge, CB2 4AT UK.
- Abbreviations:
- AD
- Alzheimer's disease
- AChE
- acetylcholinesterase
- AChEI
- AChE inhibitor
- ACh
- acetylcholine
- NE
- norepinephrine
- DA
- dopamine
- DOPAC
- 3,4-dihydroxyphenilacetic acid
- HVA
- homovanillic acid
- 5-HT
- 5-hydroxytryptamine
- 5-HIAA
- 5-hydroxyindolacetic acid
- GABA
- γ-aminobutyric acid
- FOB
- functional observational battery
- Received February 3, 2000.
- Accepted March 21, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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