Abstract：
The synthesis and pharmacological activity of a new series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as sigma-1 receptor (σ1R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ1R agonist (14qR) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ1R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ1R association assay, induces neuron viability in an in vitro model of β-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aβ peptide in rats after oral treatment, altogether making 14qR (WLB-87848) an interesting candidate for neuroprotection.
摘要：
报道了一系列新的噻吩并[2,3-d]嘧啶-4（3H）-酮衍生物作为sigma-1受体（σ1R）配体的合成和药理活性。高通量筛选程序的打击演变成一种高效和选择性的σ1R激动剂（14qR），其中包含一个游离的NH基团作为正电离部分，不符合σ1R通常的药理作用。该化合物表现出良好的物理化学和ADMET特性，显示结合免疫球蛋白蛋白/σ1R缔合测定中的激动剂谱，在β-淀粉样肽中毒的体外模型中诱导神经元活力，并显示了口服治疗后海马注射Aβ肽引起的大鼠识别记忆障碍的阳性结果，使14qR（WLB-87848）成为神经保护的有趣候选者。
