Discovery of benzamide analogs as negative allosteric modulators of human neuronal nicotinic receptors: pharmacophore modeling and structure-activity relationship studies.
Discovery of benzamide analogs as negative allosteric modulators of human neuronal nicotinic receptors: pharmacophore modeling and structure-activity relationship studies.
复制标题
发现苯甲酰胺类似物作为人类神经元烟碱受体的负变构调节剂：药效团建模和结构-活性关系研究。
DOI：
10.1016/j.bmc.2013.03.082
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发表时间：
2013
影响因子：
3.5
通讯作者：
McKay,DennisB
中科院分区：
文献类型：
--
作者：
Yi,Bitna;Long,Sihui;González-Cestari,TatianaF;Henderson,BrandonJ;Pavlovicz,RyanE;Werbovetz,Karl;Li,Chenglong;McKay,DennisB
本研究描述了我们正在进行的努力，以发现选择性靶向nAChR亚型的药物。我们利用知识nAChR配体和它们的结合位点，以前确定了我们的实验室通过虚拟筛选和确定苯甲酰胺类似物作为一种新的化学类的神经元烟碱受体（nAChR）配体。先导分子化合物1（4-（烯丙氧基）-N-（6-甲基吡啶-2-基）苯甲酰胺）抑制nAChR活性，对人α4β2 nAChR的IC 50值为6.0（3.4-10.6）μM，对人α3β4 nAChR的偏好性为2.5倍。化合物1的26种类似物也被合成或购买用于结构-活性关系（SAR）研究，并提供了将分子的化学/结构性质与其抑制nAChR活性的能力相关的信息。这里描述的nAChRs亚型选择性配体的发现，应有助于我们了解特定的nAChR亚型在正常和病理生理状态的参与显着。
The present study describes our ongoing efforts toward the discovery of drugs that selectively target nAChR subtypes. We exploited knowledge on nAChR ligands and their binding site that were previously identified by our laboratory through virtual screenings and identified benzamide analogs as a novel chemical class of neuronal nicotinic receptor (nAChR) ligands. The lead molecule, compound 1 (4-(allyloxy)-N-(6-methylpyridin-2-yl)benzamide) inhibits nAChR activity with an IC50value of 6.0 (3.4–10.6) μM on human α4β2 nAChRs with a ∼5-fold preference against human α3β4 nAChRs. Twenty-six analogs of compound 1 were also either synthesized or purchased for structure–activity relationship (SAR) studies and provided information relating the chemical/structural properties of the molecules to their ability to inhibit nAChR activity. The discovery of subtype-selective ligands of nAChRs described here should contribute significantly to our understanding of the involvement of specific nAChR subtypes in normal and pathophysiological states.