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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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.
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Item type: Article ID code: 31624 Dates: DateEvent24 October 1997PublishedSubjects: 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: 31 May 2024 17:55 URI: https://strathprints.strath.ac.uk/id/eprint/31624