Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase ?4 Isoform Inhibitors for Male Contraception.

ABSTRACT: Na,K-ATPase ?4 is a testis-specific plasma membrane Na+ and K+ transporter expressed in sperm flagellum. Deletion of Na,K-ATPase ?4 in male mice results in complete infertility, making it an attractive target for male contraception. Na,K-ATPase ?4 is characterized by a high affinity for the cardiac glycoside ouabain. With the goal of discovering selective inhibitors of the Na,K-ATPase ?4 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 ?4, with an outstanding ?4 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 ?4 and sperm function.

SUBMITTER: Syeda SS 

PROVIDER: S-EPMC5846083 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature