Díaz José Luis, Christmann Ute, Fernández Ariadna, Torrens Antoni, Port Adriana, Pascual Rosalia, Álvarez Inés, Burgueño Javier, Monroy Xavier, Montero Ana, Balada Ariadna, Vela José Miguel, Almansa Carmen
Drug Discovery and Preclinical Development, Esteve , Baldiri Reixach, 4-8, 08028 Barcelona, Spain.
J Med Chem. 2015 Mar 12;58(5):2441-51. doi: 10.1021/jm501920g. Epub 2015 Feb 19.
The synthesis and pharmacological activity of a new series of 4-aminotriazoles as potent σ1 receptor (σ1R) ligands are reported. The compounds were prepared using a 4-5-step process, involving as a key step a click chemistry reaction between ynamides and azides. The most active compounds exhibited nanomolar potency for the σ1R, and the selectivity over the σ2R was improved on decreasing the central amine basicity. It was concluded that in order to achieve good σ1R potency a minimum lipophilicity was required, while limiting to a defined range of cLogP avoided human ether-a-go-go-related gene channel inhibition. This made the most interesting derivatives to be concentrated in a narrow margin of lipophilicity. Among them, compound 13g exhibited the most potent in vivo antinociceptive properties, which are indicative of its antagonist character.
报道了一系列新型4-氨基三唑作为强效σ1受体（σ1R）配体的合成及其药理活性。这些化合物采用4至5步合成方法制备，关键步骤是炔酰胺与叠氮化物之间的点击化学反应。活性最强的化合物对σ1R表现出纳摩尔级别的效力，并且随着中心胺碱性的降低，对σ2R的选择性得到提高。得出的结论是，为了获得良好的σ1R效力，需要最低限度的亲脂性，而将cLogP限制在一定范围内可避免对人醚-去极化相关基因通道的抑制。这使得最具吸引力的衍生物集中在较窄的亲脂性范围内。其中，化合物13g表现出最强的体内抗伤害感受特性，表明其具有拮抗剂性质。
