Villetti G

References (6)

Title : Structural determinants of Torpedo californica acetylcholinesterase inhibition by the novel and orally active carbamate based anti-alzheimer drug ganstigmine (CHF-2819) - Bartolucci_2006_J.Med.Chem_49_5051
Author(s) : Bartolucci C , Siotto M , Ghidini E , Amari G , Bolzoni PT , Racchi M , Villetti G , Delcanale M , Lamba D
Ref : Journal of Medicinal Chemistry , 49 :5051 , 2006
Abstract : Ganstigmine is an orally active, geneserine derived, carbamate-based acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The crystal structure of the ganstigmine conjugate with Torpedo californica acetylcholinesterase (TcAChE) has been determined at 2.40 A resolution, and a detailed structure-based analysis of the in vitro and ex vivo anti-AChE activity by ganstigmine and by new geneserine derivatives is presented. The carbamoyl moiety is covalently bound to the active-site serine, whereas the leaving group geneseroline is not retained in the catalytic pocket. The nitrogen atom of the carbamoyl moiety of ganstigmine is engaged in a key hydrogen-bonding interaction with the active site histidine (His440). This result offers an explanation for the inactivation of the catalytic triad and may account for the long duration of action of ganstigmine in vivo. The 3D structure also provides a structural framework for the design of compounds with improved binding affinity and pharmacological properties.
ESTHER : Bartolucci_2006_J.Med.Chem_49_5051
PubMedSearch : Bartolucci_2006_J.Med.Chem_49_5051
PubMedID: 16913695
Gene_locus related to this paper: torca-ACHE

Title : Ganstigmine and donepezil improve neurodegeneration in AD11 antinerve growth factor transgenic mice - Capsoni_2004_Am.J.Alzheimers.Dis.Other.Demen_19_153
Author(s) : Capsoni S , Giannotta S , Stebel M , Garcia AA , De Rosa R , Villetti G , Imbimbo BP , Pietra C , Cattaneo A
Ref : Am J Alzheimers Dis Other Demen , 19 :153 , 2004
Abstract : Ganstigmine (CHF2819) is an acetylcholinesterase inhibitor that increases acetylcholine in rat hippocampus and ameliorates scopolamine-induced amnesia. In this article, we examined whether and how ganstigmine might prevent or rescue the neurodegenerative phenotype in AD11 antinerve growth factor (anti-NGF) mice, a transgenic model for Alzheimer's disease. The effects of ganstigmine were compared with those obtained after administration of donepezil. Results demonstrate that intraperitoneal and oral administration of ganstigmine and donepezil can reverse the cholinergic and behavioral deficit in AD11 mice but not the amyloid and phosphotau accumulation, uncovering different mechanisms leading to neurodegeneration in AD11 mice.
ESTHER : Capsoni_2004_Am.J.Alzheimers.Dis.Other.Demen_19_153
PubMedSearch : Capsoni_2004_Am.J.Alzheimers.Dis.Other.Demen_19_153
PubMedID: 15214201

Title : Characterization of the effect of ganstigmine (CHF2819) on amyloid precursor protein metabolism in SH-SY5Y neuroblastoma cells - Mazzucchelli_2003_J.Neural.Transm.(Vienna)_110_935
Author(s) : Mazzucchelli M , Porrello E , Villetti G , Pietra C , Govoni S , Racchi M
Ref : J Neural Transm (Vienna) , 110 :935 , 2003
Abstract : We have investigated the effect of ganstigmine (CHF2819), a novel geneserine derived acetylcholinesterase (AChE) inhibitor, on the expression and metabolism of the amyloid precursor protein (APP) in neuroblastoma cell line SH-SY5Y. The rationale was based on the suggestion that cholinergic activity may also be involved in the regulation of APP metabolism. We studied the acute effect on APP metabolism following the secretion of sAPPalpha in the conditioned medium of cells. Following short term treatment (2h), ganstigmine promoted a slight increase in the release of sAPPalpha, the maximal effect approaching on average 1.5 fold baseline value. The data obtained in the long term experiments demonstrate that continuous inhibition of AchE obtained with 100 nM ganstigmine following an exposure of 24 hours did not influence APP isoforms expression. However, the compound appeared to increase the constitutive release of sAPPalpha, with a mechanism that is derived from an indirect cholinergic stimulation.
ESTHER : Mazzucchelli_2003_J.Neural.Transm.(Vienna)_110_935
PubMedSearch : Mazzucchelli_2003_J.Neural.Transm.(Vienna)_110_935
PubMedID: 12898348

Title : The protective effect of ganstigmine against amyloid beta 25-35 neurotoxicity on chicken cortical neurons is independent from the cholinesterase inhibition - Windisch_2003_Neurosci.Lett_341_181
Author(s) : Windisch M , Hutter-Paier B , Jerkovic L , Imbimbo B , Villetti G
Ref : Neuroscience Letters , 341 :181 , 2003
Abstract : Ganstigmine (CHF2819), a novel genserine derived acetylcholinesterase inhibitor and its enantiomer CHF3360 have been investigated for neuroprotective activity in two different in vitro assay systems using isolated cortical neurons from 9 day old chicken embryos. In the first in vitro model cells were lesioned by growth factor deprivation for 8 days achieved by reduced serum supplementation (2%) to the tissue culture medium. In the second lesion model neurodegeneration due to the addition of pre-aggregated beta-amyloid(25-35) has been achieved. Neuronal viability of treated neurons evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5,diphenyl tetrazolium bromid reduction assay was compared to that of untreated control cells. In a dose range between 1.0 and 10.0 microM both compounds significantly prevent progressive neuronal cell death due to growth factor deprivation. Furthermore Ganstigmine and its enantiomer in concentrations between 0.1 and 3 microM also significantly decrease neurodegeneration achieved by the addition of beta-amyloid(25-35) by approximately 50%. Dose response curves of both substances were identical concerning effect size and concentration. Because CHF3360 does not show any acetylcholine inhibitor activity in the applied dose range it is concluded that Ganstigmine provides significant neuroprotection independent from its cholinergic activity.
ESTHER : Windisch_2003_Neurosci.Lett_341_181
PubMedSearch : Windisch_2003_Neurosci.Lett_341_181
PubMedID: 12697278

Title : 4-Aminopyridine derivatives with antiamnesic activity - Andreani_2000_Eur.J.Med.Chem_35_77
Author(s) : Andreani A , Leoni A , Locatelli A , Morigi R , Rambaldi M , Pietra C , Villetti G
Ref : Eur Journal of Medicinal Chemistry , 35 :77 , 2000
Abstract : Acetylcholine (Ach) enhancement, useful in the treatment of Alzheimer's disease (AD), may be obtained by means of ion channel modulators such as 4-aminopyridine (4-AP). 4-AP is also the central ring of tacrine, the first drug approved for the treatment of AD. The synthesis and pharmacological activity of three 4-AP derivatives, prepared with the aim of improving their antiamnesic activity, is here described. In two of these compounds 4-AP is connected to 4-aminobutyric acid (GABA), whereas in the third it is connected to 2-indolinone, i.e., the skeleton of linopirdine, another Ach enhancing agent. The new compounds showed potent antiamnesic activity in comparison with piracetam.
ESTHER : Andreani_2000_Eur.J.Med.Chem_35_77
PubMedSearch : Andreani_2000_Eur.J.Med.Chem_35_77
PubMedID: 10733605

Title : Biochemical and neurobehavioral profile of CHF2819, a novel, orally active acetylcholinesterase inhibitor for Alzheimer's disease - Trabace_2000_J.Pharmacol.Exp.Ther_294_187
Author(s) : Trabace L , Cassano T , Steardo L , Pietra C , Villetti G , Kendrick KM , Cuomo V
Ref : Journal of Pharmacology & Experimental Therapeutics , 294 :187 , 2000
Abstract : 1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo inverted question mark2,3-bindol-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 gamma-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.
ESTHER : Trabace_2000_J.Pharmacol.Exp.Ther_294_187
PubMedSearch : Trabace_2000_J.Pharmacol.Exp.Ther_294_187
PubMedID: 10871311