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

M T McKenna, G R Proctor, L C Young, A L Harvey

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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.
LanguageEnglish
Pages3516-3523
Number of pages8
JournalJournal of Medicinal Chemistry
Volume40
Issue number22
DOIs
Publication statusPublished - 24 Oct 1997

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Butyrylcholinesterase
Tacrine
Cholinesterase Inhibitors
Serotonin Uptake Inhibitors
Acetylcholinesterase
Alzheimer Disease
Inhibitory Concentration 50
Serotonin
Aptitude
Cholinesterases
Cholinergic Agents
Norepinephrine
Enzymes
quinoline

Keywords

  • acetylcholinesterase
  • alzheimer disease
  • cholinesterase inhibitors
  • humans
  • magnetic resonance spectroscopy
  • molecular structure
  • serotonin uptake inhibitors
  • tacrine

Cite this

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title = "Novel tacrine analogues for potential use against Alzheimer's disease: potent and selective acetylcholinesterase inhibitors and 5-HT uptake inhibitors",
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.",
keywords = "acetylcholinesterase, alzheimer disease, cholinesterase inhibitors, humans, magnetic resonance spectroscopy, molecular structure, serotonin uptake inhibitors, tacrine",
author = "McKenna, {M T} and Proctor, {G R} and Young, {L C} and Harvey, {A L}",
year = "1997",
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language = "English",
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T1 - Novel tacrine analogues for potential use against Alzheimer's disease

T2 - Journal of Medicinal Chemistry

AU - McKenna, M T

AU - Proctor, G R

AU - Young, L C

AU - Harvey, A L

PY - 1997/10/24

Y1 - 1997/10/24

N2 - 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.

AB - 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.

KW - acetylcholinesterase

KW - alzheimer disease

KW - cholinesterase inhibitors

KW - humans

KW - magnetic resonance spectroscopy

KW - molecular structure

KW - serotonin uptake inhibitors

KW - tacrine

U2 - 10.1021/jm970150t

DO - 10.1021/jm970150t

M3 - Article

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EP - 3523

JO - Journal of Medicinal Chemistry

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SN - 0022-2623

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