Nonsteroidal compounds which bind epididymal androgen-binding protein but not the androgen receptor

Abstract

In the testis of most mammals the Sertoli cells of the seminiferous tubules secrete into the lumen an androgen-binding protein (ABP). This glycoprotein is of interest because it reflects Sertoli cell function and responsiveness to follicle-stimulating hormone¹. In addition, ABP binds testosterone produced by the Leydig cells and the hormone-protein complex reaches the epididymis² where it could play a role in sperm maturation^3–6. ABP is distinct from the androgen receptor, an intracellular protein which binds testosterone and its hormonally active metabolite 5α-dihydrotestosterone (DHT) in target tissues⁷. In some species, but not the rat, a testosterone-oestradiol binding globulin (TeBG) circulates in blood⁸. Although radio-immunoassays for TeBG⁹ and ABP¹⁰ have been developed, most methods for assaying these proteins and the androgen receptor rely on their ability to bind ³H-labelled androgens. As all three proteins bind testosterone and DHT, accurate assay of any one protein awaits development of a specific label. A specific ligand for ABP would also be very valuable for further study of the physiologic role of ABP. We¹¹ and others¹² have investigated earlier suggestions² that the binding sites on ABP and the androgen receptor have different steroid specificities. Steroids were found that have a higher affinity for ABP than for the receptor. We now report on dicyclohexane derivatives which bind with high affinity to the testosterone-binding site on ABP but do not interact with the androgen receptor.