Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception.
Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception.
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DOI：
10.1021/acs.jmedchem.7b00925
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发表时间：
2018-03-08
影响因子：
7.3
通讯作者：
Blanco G
中科院分区：
文献类型：
--
作者：
Syeda SS;Sánchez G;Hong KH;Hawkinson JE;Georg GI;Blanco G
Na，K-ATPase α4是一种在精子鞭毛中表达的睾丸特异性质膜Na+和K+转运蛋白。雄性小鼠Na，K-ATP酶α4基因缺失可导致完全不育，使其成为一个有吸引力的男性避孕靶点。Na，K-ATP酶α4对强心苷哇巴因具有高亲和力。为了发现Na，K-ATP酶α4和精子功能的选择性抑制剂，在糖基（C3）和内酯（C17）结构域对哇巴因衍生物进行了修饰。哇巴皂甙元类似物25在C17处带有苄基三唑部分，是Na，K-ATP酶α4的皮摩尔抑制剂，具有突出的α4亚型选择性特征。此外，化合物25在体外和体内降低精子活力，并影响精子膜电位，细胞内Ca 2+，pH值和运动性。这些结果证明新的哇巴菌素三唑类似物是一种有效的选择性Na，K-ATP酶α4和精子功能抑制剂。
Na,K-ATPase α4 is a testis-specific plasma membrane Na+ and K+ transporter expressed in sperm flagellum. Deletion of Na,K-ATPase α4 in male mice results in complete infertility, making it an attractive target for male contraception. Na,K-ATPase α4 is characterized by a high affinity for the cardiac glycoside ouabain. With the goal of discovering selective inhibitors of the Na,K-ATPase α4 and of sperm function, ouabain derivatives were modified at the glycone (C3) and the lactone (C17) domains. Ouabagenin analogue 25, carrying a benzyltriazole moiety at C17, is a picomolar inhibitor of Na,K-ATPase α4, with an outstanding α4 isoform selectivity profile. Moreover, compound 25 decreased sperm motility in vitro and in vivo and affected sperm membrane potential, intracellular Ca2+, pH, and hypermotility. These results proved that the new ouabagenin triazole analogue is an effective and selective inhibitor of Na,K-ATPase α4 and sperm function.
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DOI：
10.1111/j.1440-1681.2011.05590.x
发表时间：
2011-11-01
影响因子：
2.9
作者：
Clarke, Ronald J.;Fan, Xiaochen
通讯作者：
Fan, Xiaochen
影响因子：
3.5
作者：
ESPINOSA, F;DARSZON, A
通讯作者：
DARSZON, A
影响因子：
4.8
作者：
Crambert, G;Hasler, U;Geering, K
通讯作者：
Geering, K
影响因子：
2.5
作者：
Buffone, Mariano G.;Ijiri, Takashi W.;Cao, Wenlei;Merdiushev, Tanya;Aghajanian, Haig K.;Gerton, George L.
通讯作者：
Gerton, George L.
影响因子：
2.9
作者：
BLANCO, G;SANCHEZ, G;MERCER, RW
通讯作者：
MERCER, RW