Thal C

References (6)

Title : The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design - Greenblatt_2004_J.Am.Chem.Soc_126_15405
Author(s) : Greenblatt HM , Guillou C , Guenard D , Argaman A , Botti SA , Badet B , Thal C , Silman I , Sussman JL
Ref : Journal of the American Chemical Society , 126 :15405 , 2004
Abstract : Bifunctional derivatives of the alkaloid galanthamine, designed to interact with both the active site of the enzyme acetylcholinesterase (AChE) and its peripheral cation binding site, have been assayed with Torpedo californica AChE (TcAChE), and the three-dimensional structures of their complexes with the enzyme have been solved by X-ray crystallography. Differences were noted between the IC(50) values obtained for TcAChE and those for Electrophorus electricus AChE. These differences are ascribed to sequence differences in one or two residues lining the active-site gorge of the enzyme. The binding of one of the inhibitors disrupts the native conformation of one wall of the gorge, formed by the loop Trp279-Phe290. It is proposed that flexibility of this loop may permit the binding of inhibitors such as galanthamine, which are too bulky to penetrate the narrow neck of the gorge formed by Tyr121 and Phe330 as seen in the crystal structure.
ESTHER : Greenblatt_2004_J.Am.Chem.Soc_126_15405
PubMedSearch : Greenblatt_2004_J.Am.Chem.Soc_126_15405
PubMedID: 15563167
Gene_locus related to this paper: torca-ACHE

Title : (-)-9-Dehydrogalanthaminium bromide, a new cholinesterase inhibitor, enhances place and object recognition memory in young and old rats - Lamirault_2003_Neurobiol.Learn.Mem_80_113
Author(s) : Lamirault L , Guillou C , Thal C , Simon H
Ref : Neurobiol Learn Mem , 80 :113 , 2003
Abstract : In a previous study, we showed that (-)-9-dehydrogalanthaminium bromide, a synthetic galanthamine derivative, was more potent than galanthamine in inhibiting acetylcholinesterase. We studied here the action of this new compound on recognition memory in young and old rats, using a two-trial recognition task designed to test both place and object recognition. (-)-9-dehydrogalanthaminium bromide was injected (0.3, 1, and 3 mg/kg, i.p.) in young and old rats before the acquisition phase, immediately after it, or before the retrieval phase of the task, in order to determine the stage of information processing affected by the compound. (-)-9-dehydrogalanthaminium bromide improved both place and object recognition in young rats, via an enhancement of acquisition (3 mg/kg: place recognition; 1 and 3 mg/kg: object recognition) and consolidation (1 and 3 mg/kg) information processing. In old rats, (-)-9-dehydrogalanthaminium bromide improved performance by acting on the acquisition processes of place (0.3, 1, and 3 mg/kg) and object (1 and 3 mg/kg) recognition. These results provide information on the profile of activity of (-)-9-dehydrogalanthaminium bromide on memory processes, and suggest that this new compound could have utility in the treatment of cognitive dysfunction occurring in Alzheimer's disease or in the normal course of aging.
ESTHER : Lamirault_2003_Neurobiol.Learn.Mem_80_113
PubMedSearch : Lamirault_2003_Neurobiol.Learn.Mem_80_113
PubMedID: 12932426

Title : Combined treatment with galanthaminium bromide, a new cholinesterase inhibitor, and RS 67333, a partial agonist of 5-HT4 receptors, enhances place and object recognition in young adult and old rats - Lamirault_2003_Prog.Neuropsychopharmacol.Biol.Psychiatry_27_185
Author(s) : Lamirault L , Guillou C , Thal C , Simon H
Ref : Prog Neuropsychopharmacol Biological Psychiatry , 27 :185 , 2003
Abstract : The present study was designed to investigate whether a combination of a new acetylcholinesterase inhibitor we have synthesized, galanthaminium bromide, and an agonist of 5-hydroxytryptamine(4) receptors, RS 67333, at doses ineffective alone, improves performance in tasks involving place and object recognition memory. Dose responses of each compound were determined in order to select doses without effect alone. Accordingly, young adult rats were injected intraperitoneally with galanthaminium bromide (0.3 mg/kg)+RS 67333 (0.01 mg/kg), and old rats with galanthaminium bromide (0.1 mg/kg for place and 0.3 mg/kg for object recognition)+RS 67333 (1 mg/kg). Drugs were injected before the acquisition phase, immediately after it, or before the retrieval phase to determine the stage of information processing affected by treatments. Doses of galanthaminium bromide and RS 67333, without effect on their own, jointly improved both place and object recognition in young adult rats via an enhancement of acquisition and consolidation information processing. In old rats, the combined treatment enhanced performance by acting on the acquisition processes of place recognition and on the acquisition and consolidation processes of object recognition. These results indicate that combining agents that act on different neuronal targets may be more powerful than either treatment alone, enabling use of lower doses of each compound, thereby attenuating the adverse effects of the individual drugs. A bitherapeutic strategy of this kind might thus be of interest in the treatment of the cognitive deficits related to "normal" or pathological aging.
ESTHER : Lamirault_2003_Prog.Neuropsychopharmacol.Biol.Psychiatry_27_185
PubMedSearch : Lamirault_2003_Prog.Neuropsychopharmacol.Biol.Psychiatry_27_185
PubMedID: 12551743

Title : Synthesis and structure-activity relationships of open D-Ring galanthamine analogues - Herlem_2003_Bioorg.Med.Chem.Lett_13_2389
Author(s) : Herlem D , Martin MT , Thal C , Guillou C
Ref : Bioorganic & Medicinal Chemistry Lett , 13 :2389 , 2003
Abstract : Open D-ring galanthamine analogues were prepared using ring-opening reactions of the quaternarized urethane or oxazolidine functions and were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition potency.
ESTHER : Herlem_2003_Bioorg.Med.Chem.Lett_13_2389
PubMedSearch : Herlem_2003_Bioorg.Med.Chem.Lett_13_2389
PubMedID: 12824041

Title : Potent acetylcholinesterase inhibitors: design, synthesis and structure-activity relationships of alkylene linked bis-galanthamine and galanthamine-galanthaminium salts - Guillou_2000_Bioorg.Med.Chem.Lett_10_637
Author(s) : Guillou C , Mary A , Renko DZ , Gras E , Thal C
Ref : Bioorganic & Medicinal Chemistry Lett , 10 :637 , 2000
Abstract : The syntheses, the anticholinesterase activities and structure-activity relationships of homodimeric (3a-c) and heterodimeric (6a-c) alkylene linked bis-galanthamine are reported. Compounds 6b-c were found to be more potent than galanthamine and tacrine in inhibiting AChE.
ESTHER : Guillou_2000_Bioorg.Med.Chem.Lett_10_637
PubMedSearch : Guillou_2000_Bioorg.Med.Chem.Lett_10_637
PubMedID: 10762042

Title : Potent acetylcholinesterase inhibitors: design, synthesis, and structure-activity relationships of bis-interacting ligands in the galanthamine series - Mary_1998_Bioorg.Med.Chem_6_1835
Author(s) : Mary A , Renko DZ , Guillou C , Thal C
Ref : Bioorganic & Medicinal Chemistry , 6 :1835 , 1998
Abstract : New galanthamine derivatives, especially bis-interacting ligands 3-5 and 7-9 were prepared in order to interact with the catalytic and the peripheral sites of acetylcholinesterase (AChE). The synthesis, the anticholinesterase activities, and the structure-activity relationships of bis-interacting ligands are reported. Compounds 4d-e were found to be more potent than galanthamine and tacrine in inhibiting AChE.
ESTHER : Mary_1998_Bioorg.Med.Chem_6_1835
PubMedSearch : Mary_1998_Bioorg.Med.Chem_6_1835
PubMedID: 9839013