Pimozide Inhibits CatSper Activity, Impairs Hyperactivation and the Acrosome Reaction in Human Spermatozoa

Health, social, and ethical considerations highlight the need for new male contraceptives. Pimozide is an FDA approved drug known to block T-type calcium channels and which shares structural similarities with mibefradil, a proven antagonist of the CatSper channel. In this study, we examined the effect of pimozide on CatSper, a key target for non-hormonal male contraception. Molecular docking and molecular dynamics simulations were carried out to assess how pimozide binds within the channel pore, and binding energies were estimated using MM-GBSA. To determine its impact on sperm function, we evaluated hyperactivation, the acrosome reaction, and CatSper activity. Our computational analyses indicate that pimozide functions as a pore blocker of the CatSper channel. Experimental findings further support this, showing that pimozide inhibits CatSper activity, and impairs hyperactivation and the acrosome reaction in human spermatozoa. Overall, these results identify pimozide as a novel CatSper antagonist and propose a binding mode, offering a basis for the rational design of reversible, non-hormonal male contraceptives that target the CatSper channel.