Dipartimento di Scienze Chimiche, Università di Camerino, via S. Agostino 1, 62032 Camerino, Italy.
J Med Chem. 2010 Feb 11;53(3):1261-9. doi: 10.1021/jm901542q.
Conservative chemical modifications of the core structure of the lead spipethiane (1) afforded novel potent sigma(1) ligands. sigma(1) affinity and sigma(1/)sigma(2) selectivity proved to be favored by the introduction of polar functions (oxygen atom or carbonyl group) in position 3 or 4 (4-6) or by the elongation of the distance between the two hydrophobic portions of the molecule with the simultaneous presence of a carbonyl group in position 4 (8 and 9). The observed cytostatic effect against the human breast cancer cell line MCF-7/ADR, highly expressing sigma(1) receptors, and not against MCF-7, as well as the enhancement of morphine analgesia highlighted the sigma(1) antagonist profile of this series of compounds. In particular, due to its high sigma(1) affinity (pK(i) = 10.28) and sigma(1)/sigma(2) selectivity ratio (29510), compound 9 might be a novel valuable tool for sigma receptor characterization and a suitable template for the rational design of potential therapeutically useful sigma(1) antagonists.
对先导化合物螺环哌啶（1）的核心结构进行保守的化学修饰，得到了新型强效的sigma(1)配体。sigma(1)亲和力和 sigma(1/)sigma(2)选择性通过在 3 位或 4 位引入极性官能团（氧原子或羰基）（4-6）或通过延长分子两个疏水区之间的距离同时在 4 位引入羰基（8 和 9）得到改善。对高表达 sigma(1)受体的人乳腺癌 MCF-7/ADR 细胞系表现出的细胞抑制作用，以及对 MCF-7 细胞系没有作用，以及对吗啡镇痛作用的增强，突出了该系列化合物的 sigma(1)拮抗剂特性。特别是，由于其高 sigma(1)亲和力（pK(i) = 10.28）和 sigma(1)/sigma(2)选择性比值（29510），化合物 9 可能是 sigma 受体表征的新型有价值工具，也是潜在治疗上有用的 sigma(1)拮抗剂的合理设计的合适模板。
