Search:
Computing and Library Services - delivering an inspiring information environment

Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

Camps, Pelayo, El Achab, Rachid, Görbig, Diana Marina, Morral-Cardoner, Jordi, Muñoz-Torrero, Diego, Badia, Albert, Baños, Josep Eladi, Vivas, Nuria María, Barril, Xavier, Orozco, Modesto and Luque, Francisco Javier (1999) Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease. Journal of Medicinal Chemistry, 42 (17). pp. 3227-3242. ISSN 0022-2623

[img]
Preview
PDF - Published Version
Download (221kB) | Preview

    Abstract

    Eleven new 12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [tacrine (THA)−huperzine A hybrids, rac-21−31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (−)-huperzine A]. The activity of some THA−huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27−31, (−)-28, and (−)-30], which are more active than (−)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (−)-huperzine A. Most of the tested compounds 19−31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA−huperzine A hybrids: the 4-aminoquinoline subunit of (−)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (−)-huperzine A, in agreement with the absolute configurations of (−)-19 and (−)-huperzine A.

    Item Type: Article
    Additional Information: Reprinted with permission from {Journal of Medicinal Chemistry}. Copyright {1999} American Chemical Society.
    Subjects: Q Science > Q Science (General)
    Q Science > QD Chemistry
    Schools: School of Applied Sciences
    Related URLs:
    Depositing User: Sara Taylor
    Date Deposited: 28 Jun 2011 16:04
    Last Modified: 28 Jun 2011 16:14
    URI: http://eprints.hud.ac.uk/id/eprint/10813

    Document Downloads

    Downloader Countries

    More statistics for this item...

    Item control for Repository Staff only:

    View Item

    University of Huddersfield, Queensgate, Huddersfield, HD1 3DH Copyright and Disclaimer All rights reserved ©