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

Journal Article · Fri Apr 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.02.009· OSTI ID:21535273

Lee, Ga Eun; Lee, Won-Gil; Lee, Song-Yi; Lee, Cho-Rong; Park, Chul-Seung ^[1]; Chang, Sunghoe ^[2]; Park, Sung-Gyoo; Song, Mi-Ryoung ^[1]; Kim, Yong-Chul ^[1]

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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)

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

• OSTI ID: 21535273
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 252; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ADENOSINE
ATP
BIOASSAY
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CALCIUM IONS
CHARGED PARTICLES
CHEMICAL REACTIONS
DISEASES
ENZYME IMMUNOASSAY
HUMAN POPULATIONS
IMMUNOASSAY
INHIBITION
IONS
LEUKOCYTES
MATERIALS
MEDICINE
MEMBRANE PROTEINS
MONOCYTES
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
PHOSPHORYLATION
POPULATIONS
PROTEINS
RECEPTORS
RHEUMATIC DISEASES
RIBOSIDES
THERAPY