Deuther-Conrad Winnie, Diez-Iriepa Daniel, Iriepa Isabel, López-Muñoz Francisco, Martínez-Grau María Angeles, Gütschow Michael, Marco-Contelles José
Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals 04318 Leipzig Germany
Department of Organic and Inorganic Chemistry, University of Alcalá Ctra. Madrid-Barcelona, Km. 33,6, 28871 Alcalá de Henares Madrid Spain.
RSC Med Chem. 2021 May 20;12(6):1000-1004. doi: 10.1039/d1md00105a. eCollection 2021 Jun 23.
Sigma (σ) receptors represent attractive targets for the development of potential agents for the treatment of several disorders, including Alzheimer's disease and neuropathic pain. In the search for multitarget small molecules (MSMs) against such disorders, we have re-discovered chromenones as new affine σ/σ ligands. 6-(4-(Piperidin-1-yl)butoxy)-4-chromen-4-one (), a previously identified MSM with potent dual-target activities against acetylcholinesterase and monoamine oxidase B, also exhibited σ/σ affinity. 6-(3-(Azepan-1-yl)propoxy)-4-chromen-4-one () showed a value for σ of 27.2 nM (selectivity (σ/σ) = 28), combining the desired σ receptor affinity with a dual inhibitory capacity against both acetyl- and butyrylcholinesterase. 6-((5-Morpholinopentyl)oxy)-4-chromen-4-one () was almost equipotent to , an established σ receptor antagonist.
西格玛（σ）受体是开发治疗多种疾病（包括阿尔茨海默病和神经性疼痛）潜在药物的有吸引力的靶点。在寻找针对此类疾病的多靶点小分子（MSMs）过程中，我们重新发现色原酮是新型的亲和性σ/σ配体。6-(4-(哌啶-1-基)丁氧基)-4-色原酮（），一种先前鉴定的对乙酰胆碱酯酶和单胺氧化酶B具有强效双靶点活性的MSM，也表现出σ/σ亲和力。6-(3-(氮杂环庚烷-1-基)丙氧基)-4-色原酮（）显示其对σ的K i值为27.2 nM（选择性（σ/σ）= 28），将所需的σ受体亲和力与对乙酰胆碱酯酶和丁酰胆碱酯酶的双重抑制能力相结合。6-((5-吗啉代戊基)氧基)-4-色原酮（）与已有的σ受体拮抗剂几乎等效。
