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Comparative Pharmacological Study of Common NMDA Receptor Open Channel Blockers Regarding Their Affinity and Functional Activity toward GluN2A and GluN2B NMDA Receptors
ChemMedChem ( IF 3.4 ) Pub Date : 2018-02-16 , DOI: 10.1002/cmdc.201700810
Louisa Temme 1 , Dirk Schepmann 1 , Julian A. Schreiber 1 , Bastian Frehland 1 , Bernhard Wünsch 1, 2
Affiliation  

Because only a few studies have investigated the affinity and functional activity of NMDA receptor open channel blockers under the same assay conditions, a comparative study of common open channel blockers is of major interest. The pharmacological activities of MK‐801, phencyclidine (PCP), dexoxadrol, etoxadrol, (S)‐ and (R)‐ketamine, dextromethorphan, memantine, and amantadine were analyzed under uniform assay conditions. Affinity toward the PCP and ifenprodil binding sites was recorded in radioligand binding assays. GluN2A and GluN2B subtype‐specific cytoprotective activity was determined in lactate dehydrogenase (LDH) assays. The data were correlated with published IC50 values obtained in two‐electrode voltage clamp experiments. A high correlation was found between PCP affinity, ion flux inhibition, and cytoprotective activity. The channel blockers were classified into four groups showing high, moderate, low, and very low potency. Some of the open channel blockers display unexpected subtype selectivity. The comparative study allows the characterization of open channel blockers from their receptor ligand interaction via inhibition of ion flux up to overall cytoprotective activity. The subtype preference of some open channel blockers will stimulate the development of novel subtype‐selective open channel blockers with decreased side effect potential.

中文翻译:

关于它们对GluN2A和GluN2B NMDA受体的亲和力和功能活性的常见NMDA受体开放通道阻滞剂的比较药理研究

因为只有很少的研究调查了在相同测定条件下NMDA受体开放通道阻滞剂的亲和力和功能活性,所以比较关注常见的开放通道阻滞剂。在统一的测定条件下分析了MK-801,苯环利定(PCP),右旋沙多醇,依托沙醇,(S)和(R)-氯胺酮,右美沙芬,美金刚和金刚烷胺的药理活性。在放射性配体结合测定中记录了对PCP和艾芬洛地尔结合位点的亲和力。在乳酸脱氢酶(LDH)分析中确定了GluN2A和GluN2B亚型特异性的细胞保护活性。数据与已发布的IC 50相关在两电极电压钳实验中获得的值。在PCP亲和力,离子通量抑制和细胞保护活性之间发现高度相关。通道阻滞剂分为四组,分别显示高,中,低和非常低的效力。一些开放通道阻止程序显示出意外的子类型选择性。这项比较研究允许通过抑制离子通量直至总体细胞保护活性,通过受体配体相互作用来表征开放通道阻滞剂。一些开放通道阻滞剂的亚型偏好将刺激副作用可能性降低的新型亚型选择性开放通道阻滞剂的发展。
更新日期:2018-02-16
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