Prospective birth control pill for men has its origin in an arrow poison

January 17, 2018, American Chemical Society

Women have many options for oral contraceptives that are safe, effective and reversible, but despite decades of research, men have none. Now, scientists report a rat study in ACS' Journal of Medicinal Chemistry that shows they finally have a good lead for a male birth control pill. It's based on ouabain, a plant extract that African warriors and hunters traditionally used as a heart-stopping poison on their arrows. 

Two types of African plants make ouabain. Mammals also produce it in their bodies, though at lower levels that are thought to help control blood pressure; doctors sometimes prescribe small doses of the compound to treat . Ouabain disrupts the passage of sodium and calcium ions through the membrane protein Na,K-ATPases, which are are found in cell membranes and are made up of . Some subunits are found in cardiac tissue, but one type of subunit called α4 is found only in . This protein is known to be critical in fertility—at least in male mice. Ouabain binds strongly to α4, but it also binds to other Na,K-ATPase subunits, albeit less tightly. Prior clinical studies have shown that ouabain curbs fertility in men. However, ouabain itself isn't an option as a contraceptive because of the risk of heart damage. So Gunda Georg, Gustavo Blanco and colleagues set out to design ouabain analogs that are far more likely to bind to the α4 protein in sperm than to subunits found in heart tissue.  

By removing a sugar group from ouabain and also replacing its lactone group with a triazole group, the researchers created a derivative that is particularly good at zeroing in on α4 in sperm cells in rats. Once bound, it interferes with the cells' ability to swim, which is essential to its role in fertilizing an egg, the scientists showed. The compound had no toxicity in rats. The researchers say that the contraceptive effect should be reversible because α4 is only found on mature sperm cells. That means sperm cells produced after stopping treatment with the ouabain derivative shouldn't be affected.  

Explore further: Researchers identify new pathway linking the brain to high blood pressure

More information: Shameem Sultana Syeda et al. Design, Synthesis, in vitro and in vivo Evaluation of Ouabain Analogs as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception, Journal of Medicinal Chemistry (2018). DOI: 10.1021/acs.jmedchem.7b00925

Abstract
Na,K-ATPase α4 is a testis specific plasma membrane Na+ and K+ transporter expressed in the 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 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 analog 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 analog is an effective and selective inhibitor of Na,K- ATPase α4 and sperm function.

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