Development of Inhibitors For the Cation Channels of Sperm For Male Contraception

Loading...
Thumbnail Image

Persistent link to this item

Statistics
View Statistics

Journal Title

Journal ISSN

Volume Title

Title

Development of Inhibitors For the Cation Channels of Sperm For Male Contraception

Published Date

2020-05

Publisher

Type

Thesis or Dissertation

Abstract

Currently, there is an unmet need for selective, non-hormonal male contraceptive agents. The cation channels of sperm (CatSper) are sperm-specific, voltage-gated ion channels that regulate the internal calcium (Ca2+) concentration in mature spermatozoa. These channels are activated by the alkaline environment of the female reproductive tract, resulting in an influx of Ca2+ initiating hyperactivated motility (HAM) necessary for fertilization. Mutations within CatSper, as confirmed by mouse knockout studies, lead to infertility in males with no other observable phenotypes, validating CatSper as a target for male contraception. We envision that the development of CatSper inhibitors will serve as a selective, reversible, and non-hormonal means to male contraception. A 70,000 compound high-throughput screening campaign was performed, using human sperm and a Fluorescent Imaging Plate Reader (FLIPR) assay to measure Ca2+ influx yielded seven hits with micromolar potencies. Two of these hits, compounds 1 and 2, were confirmed by electrophysiology as CatSper inhibitors and selected for structure-activity relationship studies. This thesis reports on the design, synthesis, and testing of analogs related to these two hits.

Description

University of Minnesota M.S. thesis.May 2020. Major: Medicinal Chemistry. Advisor: Gunda Georg. 1 computer file (PDF); vi, 54 pages.

Related to

Replaces

License

Series/Report Number

Funding information

Isbn identifier

Doi identifier

Previously Published Citation

Suggested citation

Gabet, Brian. (2020). Development of Inhibitors For the Cation Channels of Sperm For Male Contraception. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/216085.

Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.