complex.” Following optimal binding of the steroid to its receptor, the mature complex
dissociates, releasing the chaperones and converting the steroid hormone receptor com-
plex into an activated form. The activated receptor is then phosphorylated, dimerized,
and transported into the nucleus with the aid of the D domain. Once in the nucleus, the
zinc fingers of the C domain bind to the DNA and the A/B domain effects gene activa-
tion. The synthetic response in the cell is very rapid: within 15 minutes a considerable
increase in the concentration of RNA polymerase can be detected, and within 30 minutes
induced protein synthesis is measurable. These early responses can even be triggered
by hormones that have a lower than optimal affinity for the receptor (such as estriol in
uterus, which binds much more weakly than estradiol).
The steroid–receptor complex remains in the nucleus for a limited time only, and
eventually dissociates from the chromatin. About 40% of the receptors released in this
dissociation are recycled and used again; the rest are destroyed and resynthesized.
Steroid hormones can even regulate the level of synthesis of their own receptors, and
sometimes the synthesis of other steroid receptors as well.
5.4 STEROID HORMONES: STRUCTURE AND CONFORMATION
OF AGONISTS AND ANTAGONISTS
All steroids are based on the steran (5.1) skeleton, a fully hydrogenated cyclo-pentano-
phenanthrene. Traditionally, the rings of this skeleton are labeled A, B, C, and D. All
four rings are in the chair conformation in naturally occurring steroids; additionally,
rings B, C, and D are always transwith respect to each other, whereas rings A and B
can be trans(as in cholestane,5.2) or cis(as in coprostane,5.3). It is simple to con-
ceptualize this ring anellation (fusion) if one observes the relation of substituents
(including hydrogen) on the carbon atoms common to the rings in question. For rings
A and B, the relative positions of the 19-methyl group (attached to C-10) and the hydrogen
on C-5 determine the structure, and their transorcisconfiguration is easily visualized.
In general, neighboring substituents are transif they are diaxial or diequatorial, and cis
if they are axial–equatorial. The two methyl groups on C-10 and C-13 are always axial
relative to rings B and D, with the C-10 substituent (which is not necessarily methyl)
being the conformational reference point.
A somewhat obsolete but still valid nomenclature determines substituent conforma-
tions relative to the plane of a cyclohexane-type ring; thus, the 19-methyl group in the
steroid ring system is designated βand is abovethe plane of the molecule, while H-5
in cholestane (5.2) is αandbelowthe plane. The α–βconvention for steroids must
not be compared or confused with the usual axial–equatorial convention since, with the
latter convention, the flipping of a cyclohexane ring (for example) from one chair form
to another changes the position of a βsubstituent from axial to equatorial, and vice
versa. Since a substituent designated α(orβ) will remain α(orβ) but can be either axial
or equatorial, confusion can arise. The stability, reactivity, and spectroscopy of a sub-
stituent will, however, change, depending on its axial or equatorial position. Equatorial
substituents are normally more reactive and less stable than their epimers and show
slightly different absorption spectra. The physiological and pharmacological properties
of the different molecules are also different, as might be expected.
314 MEDICINAL CHEMISTRY