Synthesis and structure-activity relationships of novel, substituted 5,6-dihydrodibenzo[a,g]quinolizinium P2X7 antagonists

Ga Eun Lee; Ho Sung Lee; So Deok Lee; Jung Ho Kim; Won Ki Kim; Yong Chul Kim

doi:10.1016/j.bmcl.2008.11.088

Synthesis and structure-activity relationships of novel, substituted 5,6-dihydrodibenzo[a,g]quinolizinium P2X₇ antagonists

Ga Eun Lee, Ho Sung Lee, So Deok Lee, Jung Ho Kim, Won Ki Kim, Yong Chul Kim

Department of Biomedical Sciences

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

30 Citations (Scopus)

Abstract

Iminium quaternary protoberberine alkaloids (QPA) have been found to be novel P2X₇ antagonists. To assess their structure-activity relationships, these compounds were modified at their R¹ and R² groups and assayed for their ability to inhibit the 2′(3′)-O-(4-benzoylbenzoyl)-ATP (BzATP)-induced uptake of fluorescent ethidium by HEK-293 cells stably expressing the human P2X₇ receptor, and their ability to inhibit BzATP-induced IL-1β release by differentiated THP-1 cells. Compounds 15a and 15d, with alkyl groups at the R¹ position, and especially compound 19h, with the 2-NO₂-4,5-dimethoxy-benzyl group at the R² position, had potent inhibitory efficacy as P2X₇ antagonists.

Original language	English
Pages (from-to)	954-958
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2008.11.088
Publication status	Published - 2009 Feb 1

Keywords

Antagonist
Ethidium uptake
Human P2X receptor
IL-1β release
Iminium quaternary protoberberine alkaloids

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2008.11.088

Cite this

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title = "Synthesis and structure-activity relationships of novel, substituted 5,6-dihydrodibenzo[a,g]quinolizinium P2X7 antagonists",

abstract = "Iminium quaternary protoberberine alkaloids (QPA) have been found to be novel P2X7 antagonists. To assess their structure-activity relationships, these compounds were modified at their R1 and R2 groups and assayed for their ability to inhibit the 2′(3′)-O-(4-benzoylbenzoyl)-ATP (BzATP)-induced uptake of fluorescent ethidium by HEK-293 cells stably expressing the human P2X7 receptor, and their ability to inhibit BzATP-induced IL-1β release by differentiated THP-1 cells. Compounds 15a and 15d, with alkyl groups at the R1 position, and especially compound 19h, with the 2-NO2-4,5-dimethoxy-benzyl group at the R2 position, had potent inhibitory efficacy as P2X7 antagonists.",

keywords = "Antagonist, Ethidium uptake, Human P2X receptor, IL-1β release, Iminium quaternary protoberberine alkaloids",

author = "Lee, {Ga Eun} and Lee, {Ho Sung} and Lee, {So Deok} and Kim, {Jung Ho} and Kim, {Won Ki} and Kim, {Yong Chul}",

note = "Funding Information: This study was supported by a grant of the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0720430) and by a research grant from the Korea Science and Engineering Foundation (R01-2006-000-10880-0). ",

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doi = "10.1016/j.bmcl.2008.11.088",

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AU - Lee, Ho Sung

AU - Lee, So Deok

AU - Kim, Jung Ho

AU - Kim, Won Ki

AU - Kim, Yong Chul

N1 - Funding Information: This study was supported by a grant of the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0720430) and by a research grant from the Korea Science and Engineering Foundation (R01-2006-000-10880-0).

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AB - Iminium quaternary protoberberine alkaloids (QPA) have been found to be novel P2X7 antagonists. To assess their structure-activity relationships, these compounds were modified at their R1 and R2 groups and assayed for their ability to inhibit the 2′(3′)-O-(4-benzoylbenzoyl)-ATP (BzATP)-induced uptake of fluorescent ethidium by HEK-293 cells stably expressing the human P2X7 receptor, and their ability to inhibit BzATP-induced IL-1β release by differentiated THP-1 cells. Compounds 15a and 15d, with alkyl groups at the R1 position, and especially compound 19h, with the 2-NO2-4,5-dimethoxy-benzyl group at the R2 position, had potent inhibitory efficacy as P2X7 antagonists.

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