Abstract：
Sigma (σ) receptor subtypes, σ1 and σ2, are targets of wide pharmaceutical interest. The σ2 receptor holds promise for the development of diagnostics and therapeutics against cancer and Alzheimer\'s disease. Nevertheless, little is known about the mechanisms activated by the σ2 receptor. To contribute to the exploitation of its therapeutic potential, we developed novel specific fluorescent ligands. Indole derivatives bearing the N-butyl-3H-spiro[isobenzofuran-1,4\'-piperidine] portion were functionalized with fluorescent tags. Nanomolar-affinity fluorescent σ ligands, spanning from green to red to near-infrared emission, were obtained. Compounds 19 (σ pan affinity) and 29 (σ2 selective), which displayed the best compromise between pharmacodynamic and photophysical properties, were investigated in flow cytometry, confocal, and live cell microscopy, demonstrating their specificity for the σ2 receptor. To the best of our knowledge, these are the first red-emitting fluorescent σ2 ligands, validated as powerful tools for the study of σ2 receptors via fluorescence-based techniques.
摘要：
西格玛（σ）受体亚型，σ1和σ2是具有广泛药学兴趣的目标。σ2受体有望开发针对癌症和阿尔茨海默病的诊断和治疗方法。然而，对σ2受体激活的机制知之甚少。为了促进其治疗潜力的开发，我们开发了新的特异性荧光配体。带有N-丁基-3H-螺[异苯并呋喃-1,4'-哌啶]部分的吲哚衍生物用荧光标签官能化。纳米摩尔亲和荧光σ配体，从绿色到红色到近红外发射，已获得。化合物19(σpan亲和力)和29(σ2选择性)，这显示了药效学和光物理性质之间的最佳折衷，在流式细胞术中进行了研究，共焦,和活细胞显微镜，证明了它们对σ2受体的特异性。据我们所知,这些是第一个发红光的荧光σ2配体，通过基于荧光的技术验证为研究σ2受体的强大工具。
