Discovery and functional characterization of N-(thiazol-2-yl)-benzamide analogs as the first class of selective antagonists of the Zinc-Activated Channel (ZAC).
Discovery and functional characterization of N-(thiazol-2-yl)-benzamide analogs as the first class of selective antagonists of the Zinc-Activated Channel (ZAC).
复制标题
DOI：
10.1016/j.bcp.2021.114782
复制
发表时间：
2021-11
影响因子：
5.8
通讯作者：
Jensen, Anders A.
中科院分区：
文献类型：
--
作者：
Madjroh, Nawid;Mellou, Eleni;Davies, Paul A.;Soderhielm, Pella C.;Jensen, Anders A.
关键词：
锌激活通道（ZAC）是五聚体配体门控离子通道的Cys环受体（Cys loop receptor，Cys loop receptor）超家族的非典型成员，具有非常不同的内源性激动剂和信号传导特性。在本研究中，在ZAC的化合物库筛选导致鉴定2-（5-溴-2-氯苯甲酰氨基）-4-甲基噻唑-5-甲酯（1）为新型ZAC拮抗剂。通过双电极电压钳电生理学对非洲爪蟾卵母细胞中表达的61种ZAC类似物进行功能表征，研究了1中ZAC活性的结构决定因素，并鉴定了比1产生更有效的ZAC抑制作用的几种类似物（IC 50值：1-3 μM）。1和N-（4-（叔丁基）噻唑-2-基）-3-氟苯甲酰胺（5a，TTFB）用于研究这类新型ZAC拮抗剂的功能特性和作用方式。TTFB是一个大致等效的拮抗剂锌+和H+诱发的ZAC信号和自发的ZAC活动，其通道阻滞的缓慢启动表明，其ZAC抑制是状态依赖性的。TTFB是一种选择性ZAC拮抗剂，在30 μM浓度下，对5-HT 3A、α3β4烟碱乙酰胆碱、α1β2γ2s GABAA或α1甘氨酸受体无显著的激动剂、拮抗剂或调节活性。1显示出对Zn 2+诱导的ZAC信号传导的很大程度上的非竞争性拮抗作用，并且TTFB被证明靶向受体的跨膜和/或细胞内结构域，这共同表明N-（噻唑-2-基）-苯甲酰胺类似物充当ZAC的负变构调节剂。我们建议，这第一类的选择性ZAC拮抗剂可以构成有用的药理学工具，在未来的探索目前不清楚阐明的生理功能，由这个神经元。
The Zinc-Activated Channel (ZAC) is an atypical member of the Cys-loop receptor (CLR) superfamily of pentameric ligand-gated ion channels, with its very different endogenous agonists and signalling properties. In this study, a compound library screening at ZAC resulted in the identification of 2-(5-bromo-2-chlorobenzamido)-4-methylthiazole-5-methyl ester (1) as a novel ZAC antagonist. The structural determinants for ZAC activity in 1 were investigated by functional characterization of 61 analogs at ZAC expressed in Xenopus oocytes by two-electrode voltage clamp electrophysiology, and couple of analogs exerting more potent ZAC inhibition than 1 were identified (IC50 values: 1–3 μM). 1 and N-(4-(tert-butyl)thiazol-2-yl)-3-fluorobenzamide (5a, TTFB) were next applied in studies of the functional properties and the mode of action of this novel class of ZAC antagonists. TTFB was a roughly equipotent antagonist of Zn+- and H+ -evoked ZAC signaling and of spontaneous ZAC activity, and the slow on-set of its channel block suggested that its ZAC inhibition is state-dependent. TTFB was found to be a selective ZAC antagonist, exhibiting no significant agonist, antagonist or modulatory activity at 5-HT3A, α3β4 nicotinic acetylcholine, α1β2γ2s GABAA or α1 glycine receptors at 30 μM. 1 displayed largely noncompetitive antagonism of Zn2+-induced ZAC signalling, and TTFB was demonstrated to target the transmembrane and/or intracellular domains of the receptor, which collectively suggests that the N-(thiazol-2-yl)-benzamide analog acts a negative allosteric modulator of ZAC. We propose that this first class of selective ZAC antagonists could constitute useful pharmacological tools in future explorations of the presently poorly elucidated physiological functions governed by this CLR.
登录
查看更多内容
影响因子：
16.6
作者：
Gielen, Marc;Thomas, Philip;Smart, Trevor G.
通讯作者：
Smart, Trevor G.
影响因子：
64.8
作者：
EISELE, JL;BERTRAND, S;BERTRAND, D
通讯作者：
BERTRAND, D
DOI：
10.1016/bs.apha.2017.03.003
发表时间：
2017-01-01
期刊：
ION CHANNELS DOWN UNDER
影响因子：
--
作者：
Chua, Han Chow;Chebib, Mary
通讯作者：
Chebib, Mary
影响因子：
2.2
作者：
Abbasi, Muhammad Athar;Raza, Hussain;Hassan, Mubashir
通讯作者：
Hassan, Mubashir
影响因子：
7.3
作者：
HALLIWELL, RF;PETERS, JA;LAMBERT, JJ
通讯作者：
LAMBERT, JJ