Adjudin

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Adjudin (AF-2364), also 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide, is an analogue of indazole-carboxylic acid that is of interest in the investigation for male contraception.

As shown in mature male rats, the agent induces reversible germ cell loss from the seminiferous epithelium by disrupting cell adhesion function between Sertoli and germ cells.^[1] It weakens the adhesion between the Sertoli cell and maturing sperm leading to a sloughing and loss of the latter.^[2] As it does not affect spermatogonia themselves the loss of fertility is reversible. In experiments hormonal levels (FSH, LH, testosterone) were undisturbed during administration, and normal spermatogenesis returned in 95% of the tubules of rats at 210 days after the drug had been discontinued.^[3]

When taken orally, the drug has very low bioavailability. The oral dose effective for contraception is so high that there have been side effects in the muscles and liver. Coupling an Adjudin molecule to a mutant form of follicle-stimulating hormone may solve this problem.^[4] The mutant FSH is modified such that it not longer induces Inhibin B production, but the membrane-bound FSH receptors on Sertoli cells still bind to it, delivering the Adjudin directly to the target cells.

[edit] References

^ Dolores D. Mruk and C. Yan Cheng. Sertoli-Sertoli and Sertoli-Germ Cell Interactions and Their Significance in Germ Cell Movement in the Seminiferous Epithelium during Spermatogenesis. Endocrine Reviews (2004) 25 (5): 747-806
^ Cheng CY, Mruk D, Silvestrini B, Bonanomi M, Wong CH, Siu MK, Lee NP, Lui WY, Mo MY. AF-2364 [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide] is a potential male contraceptive: a review of recent data. Contraception. 2005 Oct;72(4):251-61. PMID 16181968
^ Grima J, Silvestrini B, Cheng CY. Reversible inhibition of spermatogenesis in rats using a new male contraceptive, 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide. Biol Reprod. 2001 May;64(5):1500-8. PMID 11319158
^ Future male 'pill' targets testicles New Scientist, 29 October 2006, citing Mruk DD, Wong CH, Silvestrini B, Cheng CY. A male contraceptive targeting germ cell adhesion. Nature Medicine advance access 29 October 2006 (DOI: 10.1038/nm1420)