MIPS Research Summaries: First safe, effective and convenient male contraceptive one step close to becoming a reality

The hunt for male contraceptive targets has mainly focused on hormonal targets or mechanisms that render sperm dysfunctional, but such strategies are associated with intolerable side effects,  including sexual dysfunction, mood changes and changes in body shape.

The team at MIPS, led by Professor Sabatino Ventura,  has previously reported that genetic deletion of the two proteins that mediate the transport of sperm from its storage site in the epididymis to the urethra during ejaculation, the α1A-adrenoceptor and P2X1-purinoceptor, resulted in infertile male mice. However, these mice exhibited normal sexual behaviour and the sperm extracted from their epididymis were normal, suggesting that a contraceptive method using this mechanism may be easily reversible. The infertile male mice were also free from physiological and behavioural side effects, suggesting that blockade of the α1A-adrenoceptor and P2X1-purinoceptor may represent a potential dual target for the development of a nonhormonal, pharmacological and safe method of male contraception.

Unfortunately, there are currently no suitable pharmacological agents that block P2X1-purinoceptors. Therefore, the MIPS researchers aimed to generate a P2X1-purinoceptor antagonist suitable for use in humans. Professor Jonathan Baell and his team of medicinal chemists synthesized a series of compounds that were screened for P2X1-purinoreceptor antagonism in isolated preparations of rat vas deferens by our team of drug discovery biologists. A subset of the synthesized molecules was identified to be highly active. Additionally, these potent compounds were found to not affect other biological mechanisms that might cause side effects. These results have contributed to a chemical profile for the P2X1-purinoceptor that will inform future designs of even more potent antagonists taking us closer to the development of the first safe, convenient and effective male contraceptive.

The research described was funded by the Male Contraceptive Initiative.

The original article is available through open access thanks to The Bill and Melinda Gates Foundation, The Male Contraceptive Initiative and The Society for the Study of Reproduction (SSR): https://academic.oup.com/biolreprod/article/103/2/323/5869664