CHF2819: Pharmacological profile of a novel acetylcholinesterase inhibitor

Department of Pharmacology and Human Physiology, Medical School, University of Bari, Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy. .
CNS Drug Reviews (Impact Factor: 4.92). 02/2002; 8(1):53-69. DOI: 10.1111/j.1527-3458.2002.tb00215.x
Source: PubMed


CHF2819 is a novel orally active acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD). CHF2819 is a selective inhibitor of AChE, it is 115 times more potent against this enzyme than against butyrylcholinesterase (BuChE). Moreover, CHF2819 is more selective for inhibition of central (brain) AChE than peripheral (heart) AChE. In vivo CHF2819, 0.5, 1.5, and 4.5 mg/kg p.o., significantly and in dose-dependent manner increased acetylcholine (ACh) levels in hippocampus of young adult rats. Moreover, aging animals, with lower basal ACh levels than young adult rats, also exhibit a marked increase in hippocampal levels of this neurotransmitter after administration of CHF2819. At 1.5 mg/kg p.o. CHF2819 attenuated scopolamine-induced amnesia in a passive avoidance task. Furthermore, it decreased dopamine (DA) levels and increased extracellular levels of 5-hydroxytryptamine (5-HT) in the hippocampus, without modifying norepinephrine (NE) levels. By oral administration to young adult rats CHF2819 did not affect extracellular hippocampal levels of glutamate (Glu), aspartate (Asp), gamma-aminobutyric acid (GABA), taurine (Tau), arginine (Arg) or citrulline (Cit). Functional observational battery (FOB) screening demonstrated 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 endpoints (body weight and temperature). CHF2819 induced, however, involuntary motor movements (ranging from mild tremors to myoclonic jerks) in a dose-dependent manner. The neurochemical and behavioral profiles of CHF2819 suggest that this orally active novel AChEI could be of clinical interest for the treatment of Alzheimer-type dementia associated with multiple neurotransmitter abnormalities in the brain. In particular, CHF2819 might be a useful therapeutic drug for AD patients with cognitive impairment accompanied by depression.

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    • "Although the hybrid, multifunctional ChEIs represent a novel approach whose usefulness remains to be proved, the confirmation of a useful, although moderate, clinical efficacy of the available ChEIs, donepezil, rivastigmine and galantamine , and the growing number of patients who need these drugs, are strong reasons that prompt the development of new " conventional " ChEIs. Among them, are the already mentioned phenserine [87] and gangstigmine [88], the selective BuChE inhibitor, cymserine [49], as well as new donepezil and galantamine derivatives [86]. Whether these compounds will demonstrate new actions beyond ChE inhibition remains to be determined. "
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    ABSTRACT: Cholinesterase inhibitors (ChEIs) were introduced in the therapy of Alzheimer Disease (AD) in the nineteen nineties with great expectations. The hopes and large interest raised by these drugs are well demonstrated by 12,000 references listed by PubMed under 'ChEI' for 1995-2007. The list is reduced to 2500 if we confine ourselves to 'ChEIs and dementia'. Of them, about 500 were published in the last two years. Whereas an increase in brain acetylcholine and an improvement of cognitive deficits have been consistently demonstrated in animal models of AD, from aging rats to transgenic mice, the clinical effectiveness of ChEIs has been and is still a matter of contrasting opinions. These range from the negative conclusions of the AD2000 trial on donepezil, claiming that it is not cost effective, with benefits below a minimally relevant threshold, to the NICE appraisal of 2007 declaring that donepezil, rivastigmine, galantamine are efficacious for mild to moderate AD, irrespective of their different selectivity for acetyl- (AChE) and butyrylcholinesterase (BuChE). The possibility that ChEIs may exert their effects through mechanisms beyond cholinesterase inhibition has been envisaged. However, according to the information presented in this review, the "classical" ChEIs, donepezil, rivastigmine and galantamine, show no pharmacological actions beyond cholinesterase inhibition which may play an important role in their therapeutic efficacy. The diverging opinions on clinical efficacy do not discourage from developing new ChEIs, and particularly the so called multifunctional ChEIs. They represent the future of the cholinergic therapy for AD but other indications for these drugs may be considered, including vascular dementia, mild cognitive impairment, and the ethically sensitive improvement of memory and learning in healthy subjects.
    Current Alzheimer research 05/2009; 6(2):86-96. DOI:10.2174/156720509787602861 · 3.89 Impact Factor
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    • "Ganstigmine inhibited brain AChE, ED 50 S (with 95% confidence limits) being 1.5 (0.4–3.7) mg/kg p.o. In the heart homogenates, ganstigmine was almost inactive [2]. Our recent in vivo studies have demonstrated that, in addition to a marked increase in the extracellular concentrations of acetylcholine (ACh) in the hippocampus of both young and aged rats induced by the oral administration of ganstigmine, this compound with AChE inhibitory properties [3] significantly elevated extracellular 5-hydroxytryptamine (5-HT) concentrations in rat hippocampus and decreased dopamine (DA) levels [4], without modifying amino acid levels, such as glutamate (Glu), aspartate (Asp), taurine (Tau), arginine (Arg) and citrulline (Cit) in the same cerebral area of freely moving rats [5]. "
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    ABSTRACT: Ganstigmine (CHF2819) is a novel, orally active acetylcholinesterase inhibitor that induces a stimulation of brain cholinergic transmission. In vivo studies show that, in rat prefrontal cortex, extracellular acetylcholine (ACh) concentrations are significantly increased either after local (1 and 10 microM) or oral (1.5 and 3 mg/kg) administration. Moreover, repeated oral treatment (six consecutive days; 3 mg/kg) with ganstigmine significantly increases basal extracellular concentrations of ACh in rat prefrontal cortex. Then, acute ganstigmine administration induces a significant increase in extracellular ACh concentrations (actual values) with respect to the last sample in ganstigmine-treated rats. Concentrations of serotonin (5-HT) and noradrenaline (NA) are not affected by any oral dose of ganstigmine (1.5 and 3 mg/kg) used. Moreover, levels of dopamine (DA) and metabolites are not modified either. Basal extracellular concentrations of 5-HT, NA, DA and metabolites are not affected by repeated (six consecutive days) ganstigmine treatment (3 mg/kg). Furthermore, there is no effect of the challenge dose of ganstigmine (3 mg/kg) on 5-HT, NA, DA and metabolites levels. Finally, ganstigmine reverses the scopolamine-induced deficits of habituation and non-spatial working memory in rats. Taken together, these findings suggest that ganstigmine appears to be a suitable candidate for the treatment of the cholinergic deficit in patients with Alzheimer's disease.
    Pharmacological Research 11/2007; 56(4):288-94. DOI:10.1016/j.phrs.2007.07.006 · 4.41 Impact Factor
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    • "Thus, the development of novel AChEIs that are tolerable and relatively safe remains a therapeutic goal. This article reviews the available data on the biochemical and neurobehavioral profile of CHF2819 (Ganstigmine, Fig. 1), a novel geneserine derivative with AChE inhibitory activity [Pietra et al., 1999; Trabace et al., 2002]. Geneserine is one of the major alkaloids found in Calabar beans and shows different degrees of AChE inhibitory activity. "
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    ABSTRACT: (-)-(3aS,8aS,1S)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol-2′-ethylphenylcarbamate N-oxide hydrochloride (CHF2819) is a novel, orally active acetylcholinesterase inhibitor (AChEI) for Alzheimer's disease (AD). CHF2819 appears as a selective inhibitor of AChE, being 115 times more potent against this enzyme than butyrylcholinesterase (BuChE). Moreover, CHF2819 appears more selective for inhibiting central (brain) than peripheral (heart) AChE. In vivo studies show that CHF2819 significantly increases acetylcholine (ACh) levels in young adult rat hippocampus in a dose-dependent manner. Moreover, aged animals exhibit a marked increase in hippocampal concentrations of this neurotransmitter after the administration of CHF2819. This compound attenuates scopolamine-induced amnesia in a passive avoidance task. Furthermore, CHF2819 induces a significant decrease in dopamine (DA) levels and a significant elevation of hippocampal extracellular concentrations of 5-hydroxytryptamine (5-HT), while it does not modify noradrenaline (NA) levels. Oral administration of CHF2819 does not affect hippocampal extracellular glutamate (Glu), aspartate (Asp), -aminobutyric acid (GABA), taurine (Tau), arginine (Arg), and citrulline (Cit) concentrations of young adult rats. Functional observational battery (FOB) 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 endpoints. However, this compound induces involuntary motor movements in a dose-dependent manner. In conclusion, the neurochemical and behavioral profile of CHF2819 suggests that this orally active novel AChEI could be of clinical interest for the treatment of Alzheimer-type dementia associated with multiple neurotransmitter abnormalities in the brain. In particular, CHF2819 might be a useful therapeutic drug for AD patients in which the cognitive impairment is accompanied by a depressive syndrome. Drug Dev. Res. 56:354–368, 2002. © 2002 Wiley-Liss, Inc.
    Drug Development Research 06/2002; 56(3):354 - 368. DOI:10.1002/ddr.10088 · 0.77 Impact Factor
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