Synthesis and structure-activity relationship studies of tyrosine-based antagonists at the human P2X7 receptor

被引：18
作者：
Lee, Ga Eun
Joshi, Bhalchandra V.
Chen, Wangzhong
Jeong, Lak Shin
Moon, Hyung Ryong
Jacobson, Kenneth A.
Kim, Yong-Chul
机构：
[1] GIST, Dept Life Sci, Kwangju 500712, South Korea
[2] NIH, Natl Inst Diab & Digest & Kidney Dis, Lab Bioorg Chem, Bethesda, MD USA
[3] Ewha Womans Univ, Coll Pharm, Lab Med Chem, Seoul 120750, South Korea
[4] Pusan Natl Univ, Coll Pharm, Pusan 609735, South Korea
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 02期
关键词：
P2X(7) receptor; tyrosine-based antagonists; ethidium bromide uptake; IL-1 beta release;
D O I：
10.1016/j.bmcl.2007.11.077
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Analogues of the P2X(7) receptor antagonist KN-62, modified at the piperazine and arylsulfonyl groups, were synthesized and assayed at the human P2X(7) receptor for inhibition of BzATP-induced effects, that is, uptake of a fluorescent dye (ethidium bromide) in stably transfected HEK293 cells and IL-1 beta release in differentiated THP-1 cells. Substitution of the arylsulfonyl, moiety with a nitro group increased antagonistic potency relative to methyl substitution, such that compound 21 was slightly more potent than KN-62. Substitution with D-tyrosine in 36 and sterically bulky tyrosyl 3,5-dimethyl groups in 9 enhanced antagonistic potency. (c) 2007 Elsevier Ltd. All rights reserved.
引用
收藏
页码：571 / 575
页数：5
相关论文
共 27 条
[1]   Novel P2X7 receptor antagonists [J].
Alcaraz, L ;
Baxter, A ;
Bent, J ;
Bowers, K ;
Braddock, M ;
Cladingboel, D ;
Donald, D ;
Fagura, M ;
Furber, M ;
Laurent, C ;
Lawson, M ;
Mortimore, M ;
McCormick, M ;
Roberts, N ;
Robertson, M .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (22) :4043-4046
[2]   Synthesis and biological activity of N-arylpiperazine-modified analogues of KN-62, a potent antagonist of the purinergic P2X7 receptor [J].
Baraldi, PG ;
Nuñez, MD ;
Morelli, A ;
Falzoni, S ;
Di Virgilio, F ;
Romagnoli, R .
JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (08) :1318-1329
[3]   Agonists and antagonists acting at P2X7 receptor [J].
Baraldi, PG ;
Di Virgilio, F ;
Romagnoli, R .
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2004, 4 (16) :1707-1717
[4]   Synthesis of conformationally constrained analogues of KN62, a potent antagonist of the P2X7-receptor [J].
Baraldi, PG ;
Romagnoli, R ;
Tabrizi, MA ;
Falzoni, S ;
Di Virgilio, F .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (07) :681-684
[5]   Functionalized congeners of tyrosine-based P2X7 receptor antagonists:: Probing multiple sites for linking and dimerization [J].
Chen, WZ ;
Ravi, RG ;
Kertesy, SB ;
Dubyak, GR ;
Jacobson, KA .
BIOCONJUGATE CHEMISTRY, 2002, 13 (05) :1100-1111
[6]   THE EFFECTS OF KN62, A CA2+/CALMODULIN-DEPENDENT PROTEIN-KINASE-II INHIBITOR, ON ADRENOCORTICAL CELL ALDOSTERONE PRODUCTION [J].
CLYNE, CD ;
NGUYEN, A ;
RAINEY, WE .
ENDOCRINE RESEARCH, 1995, 21 (1-2) :259-265
[7]   Cutting edge:: The nucleotide receptor P2X7 contains multiple protein- and lipid-interaction motifs including a potential binding site for bacterial lipopolysaccharide [J].
Denlinger, LC ;
Fisette, PL ;
Sommer, JA ;
Watters, JJ ;
Prabhu, U ;
Dubyak, GR ;
Proctor, RA ;
Bertics, PJ .
JOURNAL OF IMMUNOLOGY, 2001, 167 (04) :1871-1876
[8]  
Di Virgilio F, 1999, PROG BRAIN RES, V120, P355
[9]   THE P2Z PURINOCEPTOR - AN INTRIGUING ROLE IN IMMUNITY, INFLAMMATION AND CELL-DEATH [J].
DIVIRGILIO, F .
IMMUNOLOGY TODAY, 1995, 16 (11) :524-528
[10]   The P2X7 receptor:: A key player in IL-1 processing and release [J].
Ferrari, Davide ;
Pizzirani, Cinzia ;
Adinolfi, Elena ;
Lemoli, Roberto M. ;
Curti, Antonio ;
Idzko, Marco ;
Panther, Elisabeth ;
Di Virgilio, Francesco .
JOURNAL OF IMMUNOLOGY, 2006, 176 (07) :3877-3883
123