Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333
Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333
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DOI：
10.1016/j.ejmech.2014.07.029
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发表时间：
2014-09-12
影响因子：
6.7
通讯作者：
Kassiou, Michael
中科院分区：
文献类型：
--
作者：
Beinat, Corinne;Reekie, Tristan;Kassiou, Michael
一些实验证据支持alpha（7）nAChR参与精神分裂症和阿尔茨海默病。α 7 nAChR的调节剂已被广泛综述用于治疗与这些病理相关的认知缺陷。SEN12333代表一种新型α 7 nAChR激动剂化学型，具有降低副作用的潜力，但需要进一步的SAR探索。本工作研究了SEN12333的酰胺键，特别是它的连接和取代与四唑功能，一个已知的顺式酰胺电子等排体。结果揭示了SEN12333的原始酰胺键连接性有利于对α 7 nAChR的结合亲和力和激动剂活性。四唑等排体的使用完全消除了亲和力和功能活性，并表明SEN12333以线性构象结合。本文报道的结果还表明，5EN 12333的末端芳环内的吡啶氮对于结合亲和力或功能活性不是必需的。需要进一步进行涉及操作SEN12333中所含其他部分的SAR研究。(c)2014年Elsevier Masson SAS。All rights reserved.
Several lines of experimental evidence support the involvement of the alpha(7) nAChR in schizophrenia and Alzheimer's disease. Modulators of the alpha 7 nAChR have been extensively reviewed for the treatment of the cognitive deficits associated with these pathologies. SEN12333 represents a novel alpha 7 nAChR agonist chemotype with potential for reduced side effects but requiring further SAR exploration. The present work investigates the amide bond of SEN12333, specifically its connectivity and replacement with the tetrazole functionality, a known cis amide isostere. The results reveal the original amide bond connectivity of SEN12333 to be favorable for binding affinity and agonist activity at alpha 7 nAChRs. The use of a tetrazole isostere completely abolishes affinity and functional activity and suggests that SEN12333 binds in a linear conformation. Results reported herein also suggest the pyridine nitrogen within the terminal aromatic ring of 5EN12333 is not essential for binding affinity or functional activity. Further SAR investigations involving manipulation of other moieties contained within SEN12333 are warranted. (c) 2014 Elsevier Masson SAS. All rights reserved.