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Preclinical progress with CHF2819, a novel orally active acetylcholinesterase inhibitor
Author(s) -
Cassano Tommaso,
Carratù M. Rosaria,
Coluccia Addolorata,
Di Giovanni Vincenzo,
Steardo Luca,
Cuomo Vincenzo,
Trabace Luigia
Publication year - 2002
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.10088
Subject(s) - acetylcholinesterase , acetylcholine , neurochemical , neurotransmitter , chemistry , pharmacology , hippocampal formation , medicine , cholinergic , acetylcholinesterase inhibitor , endocrinology , taurine , biochemistry , central nervous system , enzyme , amino acid
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), γ‐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.