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 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 : PubMed
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.
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 L, Guillou C, Thal C, Simon H Ref: Prog Neuropsychopharmacol Biological Psychiatry, 27:185, 2003 : PubMed
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.
Title: Potent acetylcholinesterase inhibitors: design, synthesis, and structure-activity relationships of bis-interacting ligands in the galanthamine series Mary A, Renko DZ, Guillou C, Thal C Ref: Bioorganic & Medicinal Chemistry, 6:1835, 1998 : PubMed
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.
