331,000 unintended pregnancies are conceived every day yet, there are only two male contraceptives available. A novel target for male contraception is the P2X1 receptor which is genetically validated but further studies are held back by a lack of potent P2X1 receptor antagonists. To accelerate drug discovery efforts at the P2X1 receptor this project aims to solve a high-resolution structure of the P2X1 receptor and use this information to guide the design of highly potent P2X1 receptor antagonists. Full-length human P2X1 receptor was purified using a membrane purification preparation. Cryogenic transmission electron microscopy (cryo-EM) was used to solve the P2X1 receptor structure. P2X1 receptor antagonists were validated using a HEK293 P2X1 expressing cell line in an intracellular calcium mobilisation assay and a radioligand binding assay. Initial cryo-EM images of the P2X1 receptor revealed severe preferred orientation of the receptor in vitreous ice. The addition of a secondary detergent, fluorinated FOS-Choline-8, significantly reduced preferred orientation which assisted in obtaining a 1.96 Å structure of the P2X1 receptor in an ATP-bound state. The activity of P2X1 receptor antagonists were validated in pharmacology assays. The next step is to generate novel and more effective P2X1 receptor antagonists leveraging our high-resolution P2X1 receptor structure and optimised cryo-EM workflow.