Selective acetylcholinesterase inhibitors derived from muscle relaxant dantrolene.

Abstract:

:Dantrolene, the only therapeutic agent for malignant hyperthermia, is known to have not only a muscle relaxant effect, but also a neuroprotective effect and Alzheimer's disease improving effect. Recently, it has been reported that dantrolene has a weak inhibitory effect on acetylcholinesterase (AChE), which is a therapeutic drug target for Alzheimer's disease. Thus, we focused on developing of AChE inhibitors with benzylpiperidine/piperazine moieties that are based on the dantrolene skeleton. Several derivatives showed an inhibitory activity. Among them, ortho-nitro derivative 8c showed the most potent inhibitory activity with the IC50 value of 34.2 nM. Furthermore, Lineweaver-Burk plot analysis indicated that 8c is AChE-selective inhibitor, which shows only a weak inhibitory effect on butyrylcholinesterase (BuChE) and a non-competitive inhibition.

journal_name

Bioorg Med Chem Lett

authors

Aoyama H,Doura T

doi

10.1016/j.bmcl.2019.126888

subject

Has Abstract

pub_date

2020-02-15 00:00:00

pages

126888

issue

4

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(19)30866-2

journal_volume

30

pub_type

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