Bimodal binding and free energy of the progesterone receptor in the induction of female sexual receptivity by progesterone and synthetic progestins

Synthetic progestins (SPs) are used for regulation of fertility, contraception and hormone replacement therapy. The acetylated medroxyprogesterone (MPA), megestrol (MGA) and chlormadinone (CLA) are related to progesterone (P). Other SPs are 19-nortestosterone derivatives such as: norethisterone (NET), norethynodrel (NED) or the 13-ethyl gonane, levonorgestrel (LNG). We studied MPA, NET, NED and LNG in a dose-response manner to induce sexual receptivity in rats. Results showed that MPA, NET and NED act as partial agonists, with similar or lower potency than P. However, LNG is a full agonist. Additionally, the molecules of MPA, MGA, CLA, NET, NED, LNG, and P, were submitted to computer calculations at ab initio quantum mechanics theory, to obtain their electronic structure and molecular properties. The aim was to correlate their behavioral effect with their physicochemical properties. In addition, the crystals of P, NET and LNG bound to the progesterone receptor (PR) were studied. The PR crystallizes as a dimer forming two monomers (mA and mB), in which Gln725 interacts in either of two possible ways with the C3-carbonyl pharmacophore of progestins. P binds differentially to both PR monomers, while NET binds exclusively as mA and LNG binds only as mB in both monomers with no difference. Energetically, binding of LNG and P to mB, is more favorable than that of NET and P to mA. Consequently, this bimodal mechanism increases the action possibilities of SPs on biological systems. Interestingly, progestin potency depends mostly on local molecular structure and electronic features, prevailing over total molecular properties. © 2012 Elsevier Ltd. All rights reserved.