Novel tacrine analogues for potential use against Alzheimer's disease : potent and selective acetylcholinesterase inhibitors and 5-HT uptake inhibitors

McKenna, M T and Proctor, G R and Young, L C and Harvey, A L (1997) Novel tacrine analogues for potential use against Alzheimer's disease : potent and selective acetylcholinesterase inhibitors and 5-HT uptake inhibitors. Journal of Medicinal Chemistry, 40 (22). pp. 3516-3523. ISSN 0022-2623 (https://doi.org/10.1021/jm970150t)

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Abstract

Several novel analogues of tacrine have been synthesized and tested for their ability to inhibit acetylcholinesterase, butyrylcholinesterase, and neuronal uptake of 5-HT (serotonin) and noradrenaline. Changes in the size of the carbocyclic ring of tacrine produced modest potency against cholinesterase enzymes. Addition of a fourth ring resulted in compounds with marked selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase (BChE): e.g. 6-amino-4,5-benzo-5H-cyclopenta[1,2-b]-quinoline (14a) had an IC50 of 0.35 microM against AChE and 3.1 microM against BChE. Some tetracyclic compounds are 100-400 times more active than tacrine as inhibitors of neuronal uptake of serotonin, in particular 13-amino-6,7-dihydro-5H-benzo-[3,4]cyclohepta[1,2-b]quinoline (18), which had an IC50 of 20 nM. These compounds would be expected to facilitate both cholinergic and monoaminergic transmission. They should be worth investigating in models of memory impairment.

  • Item type:Article
    ID code:31624
    Dates:
    Date
    Event
    24 October 1997
    Published
    Keywords:acetylcholinesterase, alzheimer disease, cholinesterase inhibitors, humans, magnetic resonance spectroscopy, molecular structure, serotonin uptake inhibitors, tacrine, Therapeutics. Pharmacology, Drug Discovery, Molecular Medicine
    Subjects:Medicine > Therapeutics. Pharmacology
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:13 Jul 2011 08:56
    Last modified:27 Aug 2021 02:49
    URI:https://strathprints.strath.ac.uk/id/eprint/31624
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