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J Med Chem. 2006 Jun 15;49(12):3659-66. doi: 10.1021/jm051202e.
2
The P2X7 receptor: a key player in IL-1 processing and release.P2X7受体：白细胞介素-1加工与释放中的关键因子。
J Immunol. 2006 Apr 1;176(7):3877-83. doi: 10.4049/jimmunol.176.7.3877.
3
Synthesis and SAR of novel 4,5-diarylimidazolines as potent P2X7 receptor antagonists.新型4,5-二芳基咪唑啉作为强效P2X7受体拮抗剂的合成与构效关系研究
Bioorg Med Chem Lett. 2005 Jan 17;15(2):435-8. doi: 10.1016/j.bmcl.2004.10.052.
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Agonists and antagonists acting at P2X7 receptor.作用于P2X7受体的激动剂和拮抗剂。
Curr Top Med Chem. 2004;4(16):1707-17. doi: 10.2174/1568026043387223.
5
Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia.P2X7受体激活的小胶质细胞产生并释放神经保护性肿瘤坏死因子。
J Neurosci. 2004 Jan 7;24(1):1-7. doi: 10.1523/JNEUROSCI.3792-03.2004.
6
Novel P2X7 receptor antagonists.
Bioorg Med Chem Lett. 2003 Nov 17;13(22):4043-6. doi: 10.1016/j.bmcl.2003.08.033.
7
Synthesis and biological activity of N-arylpiperazine-modified analogues of KN-62, a potent antagonist of the purinergic P2X7 receptor.
J Med Chem. 2003 Apr 10;46(8):1318-29. doi: 10.1021/jm021049d.
8
P2X7 receptor cell surface expression and cytolytic pore formation are regulated by a distal C-terminal region.P2X7受体的细胞表面表达和溶细胞孔形成受C末端远端区域调控。
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9
Hypertonic stress increases T cell interleukin-2 expression through a mechanism that involves ATP release, P2 receptor, and p38 MAPK activation.高渗应激通过一种涉及ATP释放、P2受体和p38丝裂原活化蛋白激酶激活的机制增加T细胞白细胞介素-2的表达。
J Biol Chem. 2003 Feb 14;278(7):4590-6. doi: 10.1074/jbc.M207868200. Epub 2002 Dec 2.
10
Molecular physiology of P2X receptors.P2X受体的分子生理学
Physiol Rev. 2002 Oct;82(4):1013-67. doi: 10.1152/physrev.00015.2002.

基于酪氨酸的人P2X7受体拮抗剂的合成及构效关系研究

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

作者信息

Lee Ga Eun, Joshi Bhalchandra V, Chen Wangzhong, Jeong Lak Shin, Moon Hyung Ryong, Jacobson Kenneth A, Kim Yong-Chul

机构信息

Department of Life Science, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea.

出版信息

Bioorg Med Chem Lett. 2008 Jan 15;18(2):571-5. doi: 10.1016/j.bmcl.2007.11.077. Epub 2007 Nov 28.

DOI:10.1016/j.bmcl.2007.11.077
PMID:18078749
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2782582/
Abstract

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-1beta 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 2,6-dimethyl groups [corrected] in 9 enhanced antagonistic potency.

摘要

合成了在哌嗪和芳基磺酰基上进行修饰的P2X(7)受体拮抗剂KN-62类似物，并在人P2X(7)受体上进行检测，以抑制BzATP诱导的效应，即稳定转染的HEK293细胞中荧光染料（溴化乙锭）的摄取以及分化的THP-1细胞中IL-1β的释放。相对于甲基取代，用硝基取代芳基磺酰基部分可提高拮抗效力，使得化合物21的效力略高于KN-62。在36位用D-酪氨酸取代以及在9位用空间位阻较大的酪氨酰2,6-二甲基取代可增强拮抗效力。