Steroid structure and function—II. Conformational transmission and receptor binding of medroxyprogesterone acetate

Abstract

The A-ring of medroxyprogesterone acetate (MPA) has been determined by single crystal X-ray analysis to be in the inverted 1β,2α half-chair conformation. Steric interaction of the 17α-acetate substituent with the 17β side chain virtually immobilizes the latter and introduces strain into the backbone that is transmitted to the primary region of flexibility in the molecule, the unsaturated A-ring. The inversion of the A-ring conformation appears to be the result of this long range influence coupled with steric strain introduced by the 6α-methyl group. The differences in overall conformation and electronic nature of the A-rings in MPA and progesterone will have a significant influence upon susceptibility to metabolism and may well be related to the 30-fold higher affinity of MPA for the progestogen receptor in the rabbit uterus. Furthermore the structure demonstrates that ring inversion does not necessitate a distortion of the 4-ene-3-one conjugation, and caution must be exercised in interpreting A-ring conformation from the ORD spectrum which is primarily a measure of ene-one helicity. Crystals of MPA (C 24H 34O 4) are monoclinic. space group P2 1, with cell dimensions a = 11.0780(5) A ̊ f, b = 10.5010(4) A ̊ . c = 9.2690(3) A ̊ and β = 103.23(3)° . The structure was solved by direct methods and refined by full-matrix least-squares procedures to a final R of 0.052.