New lead discovery for novel M_1 agonists:pharmacophore model based on DISCO computation and virtual screening

To discover new lead compounds for M1 agonists. Ten typical M1 agonists were superimposed to build a M1 agonists 3D-pharmacophore model using distance-comparisons （DISCO） method without the previous knowledge of the three-dimensional structure of M1 receptor. Virtual screening strategy was used to analyze the Available Chemicals Directory-Screening Compounds （ACD-SC） to identify possible new hits. Twenty-two compounds which fit the pharmacophore model well and are not similar with known M1 agonists were purchased in order to evaluate their M1 receptor agonist activity. One of them shows M1 receptor agonist activity with EC50 of 4.90 μmol/L and maximum response. Multiple of 10.0 which shows it worthy of further study as a new lead compound for M1 agonists.

抗老年痴呆症药物研究进展

目前研究认为，痴呆与大脑皮质和皮质下神经细胞的退化有关，准确的病因学尚无结论。已开发与开发中药物主要是胆碱酯酶抑制剂（CHEI）、M1受体激动药、防止β-淀粉蛋白（BAd）沉积药、抑制γ-分泌酶药、自由基清除药、钙拮抗剂、激素类药物等，中药研究亦取得明显进展。一些天然药物活性成分如石杉碱甲、银杏叶提取物、蛇床子素、丹酚酸等具有扩张脑血管、增加脑血流量、清除自由基、免疫调节等作用，并可通过抑制脑内胆碱酯酶活性，提高脑内兴奋性递质-乙酰胆碱含量，改善老年痴呆症患者的症状。随着自由基理论与小脑血管密切相关的深入研究，细胞因子基因工程的进一步发展及类胆碱能新药的涌现，将使AD的研究药物进一步拓宽。