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We have demonstrated that a high\u2010throughput screening (HTS) strategy and established in vitro tests can identify and characterise compounds that improve sperm motility. Here, we applied HTS to identify new compounds from a novel small molecule library that increase intracellular calcium ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>), promote human sperm cell motility, and systematically determine the mechanism of action.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>A validated HTS fluorometric [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> assay was used to screen an in\u2010house library of compounds. Trequinsin hydrochloride (a PDE3 inhibitor) was selected for detailed molecular (plate reader assays, electrophysiology, and cyclic nucleotide measurement) and functional (motility and acrosome reaction) testing in sperm from healthy volunteer donors and, where possible, patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Fluorometric assays identified trequinsin as an efficacious agonist of [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>, although less potent than progesterone. Functionally, trequinsin significantly increased cell hyperactivation and penetration into viscous medium in all donor sperm samples and cell hyperactivation in 22\/25 (88%) patient sperm samples. Trequinsin\u2010induced [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> responses were cross\u2010desensitised consistently by PGE<jats:sub>1<\/jats:sub> but not progesterone. Whole\u2010cell patch clamp electrophysiology confirmed that trequinsin activated CatSper and partly inhibited potassium channel activity. Trequinsin also increased intracellular cGMP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Trequinsin exhibits a novel pharmacological profile in human sperm and may be a suitable lead compound for the development of new agents to improve patient sperm function and fertilisation potential.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14814","type":"journal-article","created":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T11:10:19Z","timestamp":1564657819000},"page":"4521-4536","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Novel pharmacological actions of trequinsin hydrochloride improve human sperm cell motility and function"],"prefix":"10.1111","volume":"176","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8623-0709","authenticated-orcid":false,"given":"Rachel C.","family":"McBrinn","sequence":"first","affiliation":[{"name":"School of Science, Engineering and Technology Abertay University  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Fraser","sequence":"additional","affiliation":[{"name":"School of Science, Engineering and Technology Abertay University  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony G.","family":"Hope","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, School of Life Sciences University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Gray","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, School of Life Sciences University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.R.","family":"Barratt","sequence":"additional","affiliation":[{"name":"Reproductive and Developmental Biology, School of Medicine, Ninewells Hospital and Medical School University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Martins da Silva","sequence":"additional","affiliation":[{"name":"Reproductive and Developmental Biology, School of Medicine, Ninewells Hospital and Medical School University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean G.","family":"Brown","sequence":"additional","affiliation":[{"name":"School of Science, Engineering and Technology Abertay University  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0032-1312646"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/odi.12275"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","unstructured":"Alasmari W. 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