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Title: Characterization of protoberberine analogs employed as novel human P2X{sub 7} receptor antagonists

Abstract

The P2X{sub 7} receptor (P2X{sub 7}R), a member of the ATP-gated ion channel family, is regarded as a promising target for therapy of immune-related diseases including rheumatoid arthritis and chronic pain. A group of novel protoberberine analogs (compounds 3-5), discovered by screening of chemical libraries, was here investigated with respect to their function as P2X{sub 7}R antagonists. Compounds 3-5 non-competitively inhibited BzATP-induced ethidium ion influx into hP2X{sub 7}-expressing HEK293 cells, with IC{sub 50} values of 100-300 nM. This antagonistic action on the channel further confirmed that both BzATP-induced inward currents and Ca{sup 2+} influx were strongly inhibited by compounds 3-5 in patch-clamp and Ca{sup 2+} influx assays. The antagonists also effectively suppressed downstream signaling of P2X{sub 7} receptors including IL-1{beta} release and phosphorylation of ERK1/2 and p38 proteins in hP2X{sub 7}-expressing HEK293 cells or in differentiated human monocytes (THP-1 cells). Moreover, IL-2 secretion from CD3/CD28-stimulated Jurkat T cell was also dramatically inhibited by the antagonist. These results imply that novel protoberberine analogs may modulate P2X{sub 7} receptor-mediated immune responses by allosteric inhibition of the receptor. - Graphical abstract: Display Omitted

Authors:
; ; ; ;  [1];  [2]; ;  [1];  [1]
  1. School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712 (Korea, Republic of)
  2. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of)
Publication Date:
OSTI Identifier:
21535273
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 252; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2011.02.009; PII: S0041-008X(11)00055-X; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADENOSINE; ATP; CALCIUM IONS; ENZYME IMMUNOASSAY; HUMAN POPULATIONS; INHIBITION; MONOCYTES; PHOSPHORYLATION; RECEPTORS; RHEUMATIC DISEASES; THERAPY; BIOASSAY; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; BODY FLUIDS; CHARGED PARTICLES; CHEMICAL REACTIONS; DISEASES; IMMUNOASSAY; IONS; LEUKOCYTES; MATERIALS; MEDICINE; MEMBRANE PROTEINS; NUCLEOSIDES; NUCLEOTIDES; ORGANIC COMPOUNDS; POPULATIONS; PROTEINS; RIBOSIDES

Citation Formats

Lee, Ga Eun, Lee, Won-Gil, Lee, Song-Yi, Lee, Cho-Rong, Park, Chul-Seung, Chang, Sunghoe, Park, Sung-Gyoo, Song, Mi-Ryoung, and Kim, Yong-Chul, E-mail: yongchul@gist.ac.kr. Characterization of protoberberine analogs employed as novel human P2X{sub 7} receptor antagonists. United States: N. p., 2011. Web. doi:10.1016/j.taap.2011.02.009.
Lee, Ga Eun, Lee, Won-Gil, Lee, Song-Yi, Lee, Cho-Rong, Park, Chul-Seung, Chang, Sunghoe, Park, Sung-Gyoo, Song, Mi-Ryoung, & Kim, Yong-Chul, E-mail: yongchul@gist.ac.kr. Characterization of protoberberine analogs employed as novel human P2X{sub 7} receptor antagonists. United States. doi:10.1016/j.taap.2011.02.009.
Lee, Ga Eun, Lee, Won-Gil, Lee, Song-Yi, Lee, Cho-Rong, Park, Chul-Seung, Chang, Sunghoe, Park, Sung-Gyoo, Song, Mi-Ryoung, and Kim, Yong-Chul, E-mail: yongchul@gist.ac.kr. Fri . "Characterization of protoberberine analogs employed as novel human P2X{sub 7} receptor antagonists". United States. doi:10.1016/j.taap.2011.02.009.
@article{osti_21535273,
title = {Characterization of protoberberine analogs employed as novel human P2X{sub 7} receptor antagonists},
author = {Lee, Ga Eun and Lee, Won-Gil and Lee, Song-Yi and Lee, Cho-Rong and Park, Chul-Seung and Chang, Sunghoe and Park, Sung-Gyoo and Song, Mi-Ryoung and Kim, Yong-Chul, E-mail: yongchul@gist.ac.kr},
abstractNote = {The P2X{sub 7} receptor (P2X{sub 7}R), a member of the ATP-gated ion channel family, is regarded as a promising target for therapy of immune-related diseases including rheumatoid arthritis and chronic pain. A group of novel protoberberine analogs (compounds 3-5), discovered by screening of chemical libraries, was here investigated with respect to their function as P2X{sub 7}R antagonists. Compounds 3-5 non-competitively inhibited BzATP-induced ethidium ion influx into hP2X{sub 7}-expressing HEK293 cells, with IC{sub 50} values of 100-300 nM. This antagonistic action on the channel further confirmed that both BzATP-induced inward currents and Ca{sup 2+} influx were strongly inhibited by compounds 3-5 in patch-clamp and Ca{sup 2+} influx assays. The antagonists also effectively suppressed downstream signaling of P2X{sub 7} receptors including IL-1{beta} release and phosphorylation of ERK1/2 and p38 proteins in hP2X{sub 7}-expressing HEK293 cells or in differentiated human monocytes (THP-1 cells). Moreover, IL-2 secretion from CD3/CD28-stimulated Jurkat T cell was also dramatically inhibited by the antagonist. These results imply that novel protoberberine analogs may modulate P2X{sub 7} receptor-mediated immune responses by allosteric inhibition of the receptor. - Graphical abstract: Display Omitted},
doi = {10.1016/j.taap.2011.02.009},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 252,
place = {United States},
year = {Fri Apr 15 00:00:00 EDT 2011},
month = {Fri Apr 15 00:00:00 EDT 2011}
}