Molecular Structure of 18-Deoxyaldosterone and Its Relationship to Receptor Binding and Activity

18-Deoxyaldosterone possesses one-third the binding affinity of aldosterone for the cytoplasmic mineralocorticoid receptor and exhibits an approximate 2:1 antagonist to agonist ratio. Crystals of 18-deoxyaldosterone contain two molecules that differ significantly from one another in 17β-side-chain orientation, 4-en-3-one conjugation, and hydrogen bonding. The C(20)–O(20) bond is synperiplanar to C(17)–C(16) in molecule I and to C(17)–C(13) in molecule II. The latter conformation, previously observed only in the presence of a 16β-methyl or -halo substituent, has been stabilized by the fact that epoxide formation draws the C(18) methyl away from the D ring. The two conformers must be in equilibrium in solution. Both molecules of 18-deoxyaldosterone resemble aldosterone in the overall shape of the A, B, C, and E rings. Molecule II and aldosterone have similar hydrogen bonding to O(3) and nearly planar 4-en-3-one conformations. Although the D-ring composition of aldosterone and 18-deoxyaldosterone is different, the side-chain orientation of molecule I of 18-deoxyaldosterone comes closest to approximating that of aldosterone in shape and potential hydrogen-bonding geometry. Analysis of the conformations and activity of aldosterone, 18-deoxyaldosterone, and spironolactone is in agreement with the model which proposes that the A-ring end of the steroid is primarily responsible for initiating and maintaining receptor binding and D-ring variation governs agonist-antagonist response. Molecule II appears to have an A ring ideally suited to receptor binding and a side-chain orientation that would elicit little or no subsequent activity, while molecule I has the side-chain orientation that most likely contributes to the partial agonism exhibited by the molecule. The crystal structure of the hemihydrate of 18-deoxyaldosterone (a = 19.878 (3) Å, b = 30.341 (4) Å, c = 5.9951 (5) Å, P2₁2₁2₁) was determined by direct methods and refined to a final R index of 0.072.