sAC as a target for male contraceptive agents: Spermatozoa contain a testis-specific form of adenylyl cyclase (sAC) that has unique properties that make it desirable to explore as a target for male contraceptive agents. This form of the enzyme is soluble, and is the product of a gene that is different from all of the other known forms of membrane AC.

sAC is present during the developmental stages of sperm production, in spermatocytes, elongating spermatids, and spermatozoa. Most importantly, sAC knockout mice show male-specific infertility due to the production of severe motile deficient sperm. cAMP-dependent processes are important during spermatogenesis as well as for the initiation and maintenance of sperm motility. Thus, disruption of cAMP-dependent signaling also has profound effects on spermatogenesis.

With regard to recent success in the development of promising contraceptive leads, we have recently designed a highly selective inhibitor of sAC, LN-2-4, that has a EC50 of about 20 nM, whereas for testicular membrane AC activities the EC50 is 3 orders of magnitude higher, and for somatic AC isoforms, 4 orders of magnitude higher. LN-2-4 is a potent inhibitor of sperm motility in vitro and is currently being assessed by NICHD for its effect on spermatogenesis and motility of epididymal sperm.

File Number: 2005 FY 14 

Web site: http://www.medchem.ku.edu

Other Information: *State of Development* Available for licenseing.