Projects per year
Background and Purpose: Asthenozoospermia is a leading cause of male infertility, but development of pharmacological agents to improve sperm motility is hindered by the lack of effective screening platforms and knowledge of suitable molecular targets. We have demonstrated that a high-throughput 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 2+] i), promote human sperm cell motility, and systematically determine the mechanism of action. Experimental Approach: A validated HTS fluorometric [Ca 2+] i assay was used to screen an in-house 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. Key Results: Fluorometric assays identified trequinsin as an efficacious agonist of [Ca 2+] i, 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-induced [Ca 2+] i responses were cross-desensitised consistently by PGE 1 but not progesterone. Whole-cell patch clamp electrophysiology confirmed that trequinsin activated CatSper and partly inhibited potassium channel activity. Trequinsin also increased intracellular cGMP. Conclusion and Implications: 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.
|Number of pages||16|
|Journal||British Journal of Pharmacology|
|Early online date||1 Aug 2019|
|Publication status||Published - Dec 2019|
- Cyclic nucleotides
- Phosphodiesterase inhibitor
ASJC Scopus subject areas
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- 3 Finished
Physiological Studies of Sperm from Normal and Sub Fertile Men (joint with Universities of Birmingham and Durham)
Barratt, C. & Wilson, S.
1/04/13 → 1/04/16
De-Risking Innovative Drug Discovery Projects Through Portfolio Management
1/01/13 → 30/06/14