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

Research output: Contribution to journalArticle

26 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 languageEnglish
Pages (from-to)954-958
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number3
DOIs
Publication statusPublished - 2009 Feb 1

Fingerprint

Structure-Activity Relationship
Ethidium
HEK293 Cells
Interleukin-1
Alkaloids
3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate
5,6-dihydrodibenzo(a,g)quinolizinium
human P2XR receptor
protoberberine

Keywords

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

ASJC Scopus subject areas

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

Cite this

Synthesis and structure-activity relationships of novel, substituted 5,6-dihydrodibenzo[a,g]quinolizinium P2X7 antagonists. / Lee, Ga Eun; Lee, Ho Sung; Lee, So Deok; Kim, Jung Ho; Kim, Won-Ki; Kim, Yong Chul.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 19, No. 3, 01.02.2009, p. 954-958.

Research output: Contribution to journalArticle

Lee, Ga Eun ; Lee, Ho Sung ; Lee, So Deok ; Kim, Jung Ho ; Kim, Won-Ki ; Kim, Yong Chul. / Synthesis and structure-activity relationships of novel, substituted 5,6-dihydrodibenzo[a,g]quinolizinium P2X7 antagonists. In: Bioorganic and Medicinal Chemistry Letters. 2009 ; Vol. 19, No. 3. pp. 954-958.
@article{25605fed0b9c468c993faf8fbe21c674,
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 Won-Ki Kim and Kim, {Yong Chul}",
year = "2009",
month = "2",
day = "1",
doi = "10.1016/j.bmcl.2008.11.088",
language = "English",
volume = "19",
pages = "954--958",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "3",

}

TY - JOUR

T1 - Synthesis and structure-activity relationships of novel, substituted 5,6-dihydrodibenzo[a,g]quinolizinium P2X7 antagonists

AU - Lee, Ga Eun

AU - Lee, Ho Sung

AU - Lee, So Deok

AU - Kim, Jung Ho

AU - Kim, Won-Ki

AU - Kim, Yong Chul

PY - 2009/2/1

Y1 - 2009/2/1

N2 - 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.

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.

KW - Antagonist

KW - Ethidium uptake

KW - Human P2X receptor

KW - IL-1β release

KW - Iminium quaternary protoberberine alkaloids

UR - http://www.scopus.com/inward/record.url?scp=58549113754&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58549113754&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2008.11.088

DO - 10.1016/j.bmcl.2008.11.088

M3 - Article

C2 - 19110420

AN - SCOPUS:58549113754

VL - 19

SP - 954

EP - 958

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 3

ER -