Design, synthesis, and electrophysiological evaluation of NS6740 derivatives: Exploration of the structure-activity relationship for alpha7 nicotinic acetylcholine receptor silent activation.
Design, synthesis, and electrophysiological evaluation of NS6740 derivatives: Exploration of the structure-activity relationship for alpha7 nicotinic acetylcholine receptor silent activation.
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NS6740衍生物的设计，合成和电生理评估：探索α7烟碱乙酰胆碱受体无声激活的结构活性关系。
DOI：
10.1016/j.ejmech.2020.112669
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发表时间：
2020-11-01
影响因子：
6.7
通讯作者：
Dallanoce C
中科院分区：
文献类型：
--
作者：
Pismataro MC;Horenstein NA;Stokes C;Quadri M;De Amici M;Papke RL;Dallanoce C
α7烟碱型乙酰胆碱受体（nAChR）沉默激动剂能够诱导受体脱敏并促进α7代谢功能，是一种新兴的有前途的抗炎治疗药物。在此，我们报告了原型沉默激动剂NS 6740（1，4-二氮杂双环[3.2.2]壬-4-基（5-（3-（三氟甲基）-苯基）-呋喃-2基）甲酮）（1）的构效关系研究，以阐明负责α7沉默激活的配体-受体相互作用。本研究设计、合成了NS 6740片段11-16和类似物17-32，并采用双电极电压钳实验对非洲爪蟾卵母细胞表达的人α7 nAChRs进行了分析。总之，NS 6740的结构部分对于产生其独特的活性特征至关重要。二氮杂双环核对于诱导α7沉默激活至关重要，但还不足以诱导α7沉默激活。中心氢键受体核心和芳香族部分对于促进延长α7受体结合和持续脱敏至关重要。化合物13和17是有效的部分激动剂。化合物12、21、23-26和30强烈脱敏α7 nAChR，因此可能对炎症反应的额外研究感兴趣。我们获得了对进一步沉默激动剂开发有用的关键结构信息。
The α7 nicotinic acetylcholine receptor (nAChR) silent agonists, able to induce receptor desensitization and promote the α7 metabotropic function, are emerging as new promising therapeutic anti-inflammatory agents. Herein, we report the structure–activity relationship investigation of the archetypal silent agonist NS6740 (1,4-diazabicyclo[3.2.2]nonan-4-yl(5-(3-(trifluoromethyl)-phenyl)-furan-2yl)methanone) (1) to elucidate the ligand-receptor interactions responsible for the α7 silent activation. In this study, NS6740 fragments 11–16 and analogs 17–32 were designed, synthesized, and assayed on human α7 nAChRs expressed in Xenopus laevis oocytes with two-electrode voltage clamping experiments. All together the structural portions of NS6740 were critical to engender its peculiar activity profile. The diazabicyclic nucleus was essential but not sufficient for inducing α7 silent activation. The central hydrogen-bond acceptor core and the aromatic moiety were crucial for promoting prolonged α7 receptor binding and sustained desensitization. Compounds 13 and 17 were efficacious partial agonists. Compounds 12, 21, 23–26, and 30 strongly desensitized α7 nAChR and therefore may be of interest for additional investigation of inflammation responses. We gained key structural information useful for further silent agonist development.
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影响因子：
4.5
作者：
Colon-Saez, Jose O.;Yakel, Jerrel L.
通讯作者：
Yakel, Jerrel L.
影响因子：
7.3
作者：
Briggs, Clark A.;Gronlien, Jens Halvard;Gopalakrishnan, Murali
通讯作者：
Gopalakrishnan, Murali
影响因子：
3.6
作者：
Gulsevin, Alican;Papke, Roger L.;Horenstein, Nicole A.
通讯作者：
Horenstein, Nicole A.
影响因子：
4.8
作者：
King, Justin R.;Nordman, Jacob C.;Kabbani, Nadine
通讯作者：
Kabbani, Nadine
DOI：
10.1007/s11481-015-9601-5
发表时间：
2015-09
期刊：
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
影响因子：
--
作者：
Báez-Pagán CA;Delgado-Vélez M;Lasalde-Dominicci JA
通讯作者：
Lasalde-Dominicci JA