Synthesis of alkylene linked bis-THA and alkylene linked benzyl-THA as highly potent and selective inhibitors and molecular probes of acetylcholinesterase

Yuan-Ping Pang, Feng Hong, Polly Quiram, Tanya Jelacic, William Stephen Brimijoin

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Abstract

An efficient and economical synthesis of a series of rationally designed novel 9,9′-(alkane-1,-ω-diyldiimino)-1,2,3,4-tetrahydroacridines (ω = 7-10) and a second series of new analogues, 9-(ω-phenylalkylamino)-1,2,3,4-tetrahydroacridines (ω = 4-10), is reported. Compounds in the first series are found to be up to 10 000-fold more selective and 1000-fold more potent in reversibly inhibiting rat acetylcholinesterase (AChE) than the monomer, 9-amino-1,2,3,4-tetrahydroacridine (THA). Some members in the latter series (ω = 7-8) are slightly more potent than THA in inhibiting AChE but still more selective. These compounds can serve as (i) important chemical tools to evaluate the role of AChE inhibition by THA, a clinical drug, in treating Alzheimer's disease, (ii) effective, safer and low-cost insecticides and parasiticides, (iii) potential blockers of the K+ channel and the N-methyl-D-aspartate receptor channel, and perhaps (iv) improved therapeutics for Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)171-176
Number of pages6
JournalJournal of the Chemical Society - Perkin Transactions 1
Issue number2
StatePublished - Jan 21 1997

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Tacrine
Molecular Probes
Acetylcholinesterase
Antiparasitic Agents
Alkanes
Insecticides
N-Methyl-D-Aspartate Receptors
Monomers
Pharmaceutical Preparations
Costs

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

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title = "Synthesis of alkylene linked bis-THA and alkylene linked benzyl-THA as highly potent and selective inhibitors and molecular probes of acetylcholinesterase",
abstract = "An efficient and economical synthesis of a series of rationally designed novel 9,9′-(alkane-1,-ω-diyldiimino)-1,2,3,4-tetrahydroacridines (ω = 7-10) and a second series of new analogues, 9-(ω-phenylalkylamino)-1,2,3,4-tetrahydroacridines (ω = 4-10), is reported. Compounds in the first series are found to be up to 10 000-fold more selective and 1000-fold more potent in reversibly inhibiting rat acetylcholinesterase (AChE) than the monomer, 9-amino-1,2,3,4-tetrahydroacridine (THA). Some members in the latter series (ω = 7-8) are slightly more potent than THA in inhibiting AChE but still more selective. These compounds can serve as (i) important chemical tools to evaluate the role of AChE inhibition by THA, a clinical drug, in treating Alzheimer's disease, (ii) effective, safer and low-cost insecticides and parasiticides, (iii) potential blockers of the K+ channel and the N-methyl-D-aspartate receptor channel, and perhaps (iv) improved therapeutics for Alzheimer's disease.",
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T1 - Synthesis of alkylene linked bis-THA and alkylene linked benzyl-THA as highly potent and selective inhibitors and molecular probes of acetylcholinesterase

AU - Pang, Yuan-Ping

AU - Hong, Feng

AU - Quiram, Polly

AU - Jelacic, Tanya

AU - Brimijoin, William Stephen

PY - 1997/1/21

Y1 - 1997/1/21

N2 - An efficient and economical synthesis of a series of rationally designed novel 9,9′-(alkane-1,-ω-diyldiimino)-1,2,3,4-tetrahydroacridines (ω = 7-10) and a second series of new analogues, 9-(ω-phenylalkylamino)-1,2,3,4-tetrahydroacridines (ω = 4-10), is reported. Compounds in the first series are found to be up to 10 000-fold more selective and 1000-fold more potent in reversibly inhibiting rat acetylcholinesterase (AChE) than the monomer, 9-amino-1,2,3,4-tetrahydroacridine (THA). Some members in the latter series (ω = 7-8) are slightly more potent than THA in inhibiting AChE but still more selective. These compounds can serve as (i) important chemical tools to evaluate the role of AChE inhibition by THA, a clinical drug, in treating Alzheimer's disease, (ii) effective, safer and low-cost insecticides and parasiticides, (iii) potential blockers of the K+ channel and the N-methyl-D-aspartate receptor channel, and perhaps (iv) improved therapeutics for Alzheimer's disease.

AB - An efficient and economical synthesis of a series of rationally designed novel 9,9′-(alkane-1,-ω-diyldiimino)-1,2,3,4-tetrahydroacridines (ω = 7-10) and a second series of new analogues, 9-(ω-phenylalkylamino)-1,2,3,4-tetrahydroacridines (ω = 4-10), is reported. Compounds in the first series are found to be up to 10 000-fold more selective and 1000-fold more potent in reversibly inhibiting rat acetylcholinesterase (AChE) than the monomer, 9-amino-1,2,3,4-tetrahydroacridine (THA). Some members in the latter series (ω = 7-8) are slightly more potent than THA in inhibiting AChE but still more selective. These compounds can serve as (i) important chemical tools to evaluate the role of AChE inhibition by THA, a clinical drug, in treating Alzheimer's disease, (ii) effective, safer and low-cost insecticides and parasiticides, (iii) potential blockers of the K+ channel and the N-methyl-D-aspartate receptor channel, and perhaps (iv) improved therapeutics for Alzheimer's disease.

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