Bis(7)-tacrine, a novel dimeric AChE inhibitor, is a potent GABA(A) receptor antagonist

Li Chao Ying; Hong Wang; Hong Xue; Paul R. Carlier; Kowk Min Hui; Yuan Ping Pang; Zhi Wang Li; Yi Fan Han

doi:10.1097/00001756-199903170-00024

Bis(7)-tacrine, a novel dimeric AChE inhibitor, is a potent GABA(A) receptor antagonist

Li Chao Ying, Hong Wang, Hong Xue, Paul R. Carlier, Kowk Min Hui, Yuan Ping Pang, Zhi Wang Li, Yi Fan Han

Pharmacology

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Heptylene-linked bis-(9-amino-1,2,3,4-tetrahydroacridine) (bis(7)- tacrine) is a potential palliative therapeutic agent for Alzheimer's disease (AD), on the basis of its superior acetylcholinesterase (ACHE) inhibition and memory-enhancing potency relative to tacrine. In this study we report that bis(7)-tacrine exhibits a potentially complementary central nervous system action, antagonism of GABA(A) receptor function. Bis(7)tacrine displaced [³H]muscimol from rat brain membranes with an apparent K(i) of 6.0 μM; tacrine and physostigmine were shown to be 18 and 170 times less potent, respectively. In whole-cell patch-clamp recordings, bis(7)-tacrine inhibited GABA-induced inward current with an IC⁵⁰ of 5.6 μM, and shifted the GABA concentration-response curve to the right in a parallel manner. These results suggest that bis(7)-tacrine is a competitive antagonist of the GABA(A) receptor.

Original language	English (US)
Pages (from-to)	795-800
Number of pages	6
Journal	NeuroReport
Volume	10
Issue number	4
DOIs	https://doi.org/10.1097/00001756-199903170-00024
State	Published - Mar 17 1999

Keywords

Acetylcholinesterase
Bis(7)-tacrine
Cholinesterase inhibitor
GABA(A) receptor
Muscimol
Physostigmine
Tacrine

ASJC Scopus subject areas

Neuroscience(all)

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10.1097/00001756-199903170-00024

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title = "Bis(7)-tacrine, a novel dimeric AChE inhibitor, is a potent GABA(A) receptor antagonist",

abstract = "Heptylene-linked bis-(9-amino-1,2,3,4-tetrahydroacridine) (bis(7)- tacrine) is a potential palliative therapeutic agent for Alzheimer's disease (AD), on the basis of its superior acetylcholinesterase (ACHE) inhibition and memory-enhancing potency relative to tacrine. In this study we report that bis(7)-tacrine exhibits a potentially complementary central nervous system action, antagonism of GABA(A) receptor function. Bis(7)tacrine displaced [3H]muscimol from rat brain membranes with an apparent K(i) of 6.0 μM; tacrine and physostigmine were shown to be 18 and 170 times less potent, respectively. In whole-cell patch-clamp recordings, bis(7)-tacrine inhibited GABA-induced inward current with an IC50 of 5.6 μM, and shifted the GABA concentration-response curve to the right in a parallel manner. These results suggest that bis(7)-tacrine is a competitive antagonist of the GABA(A) receptor.",

keywords = "Acetylcholinesterase, Bis(7)-tacrine, Cholinesterase inhibitor, GABA(A) receptor, Muscimol, Physostigmine, Tacrine",

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AU - Chao Ying, Li

AU - Wang, Hong

AU - Xue, Hong

AU - Carlier, Paul R.

AU - Min Hui, Kowk

AU - Ping Pang, Yuan

AU - Wang Li, Zhi

AU - Fan Han, Yi

PY - 1999/3/17

Y1 - 1999/3/17

N2 - Heptylene-linked bis-(9-amino-1,2,3,4-tetrahydroacridine) (bis(7)- tacrine) is a potential palliative therapeutic agent for Alzheimer's disease (AD), on the basis of its superior acetylcholinesterase (ACHE) inhibition and memory-enhancing potency relative to tacrine. In this study we report that bis(7)-tacrine exhibits a potentially complementary central nervous system action, antagonism of GABA(A) receptor function. Bis(7)tacrine displaced [3H]muscimol from rat brain membranes with an apparent K(i) of 6.0 μM; tacrine and physostigmine were shown to be 18 and 170 times less potent, respectively. In whole-cell patch-clamp recordings, bis(7)-tacrine inhibited GABA-induced inward current with an IC50 of 5.6 μM, and shifted the GABA concentration-response curve to the right in a parallel manner. These results suggest that bis(7)-tacrine is a competitive antagonist of the GABA(A) receptor.

AB - Heptylene-linked bis-(9-amino-1,2,3,4-tetrahydroacridine) (bis(7)- tacrine) is a potential palliative therapeutic agent for Alzheimer's disease (AD), on the basis of its superior acetylcholinesterase (ACHE) inhibition and memory-enhancing potency relative to tacrine. In this study we report that bis(7)-tacrine exhibits a potentially complementary central nervous system action, antagonism of GABA(A) receptor function. Bis(7)tacrine displaced [3H]muscimol from rat brain membranes with an apparent K(i) of 6.0 μM; tacrine and physostigmine were shown to be 18 and 170 times less potent, respectively. In whole-cell patch-clamp recordings, bis(7)-tacrine inhibited GABA-induced inward current with an IC50 of 5.6 μM, and shifted the GABA concentration-response curve to the right in a parallel manner. These results suggest that bis(7)-tacrine is a competitive antagonist of the GABA(A) receptor.

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KW - Bis(7)-tacrine

KW - Cholinesterase inhibitor

KW - GABA(A) receptor

KW - Muscimol

KW - Physostigmine

KW - Tacrine

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Bis(7)-tacrine, a novel dimeric AChE inhibitor, is a potent GABA(A) receptor antagonist

Abstract

Keywords

ASJC Scopus subject areas

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