Search

• The study of the functions of mPRs requires the ligands that selectively interact only with mPRs. • For the first time, the available information on the structures of compounds interacting with mPRs was summarized and analyzed. • Main trends of steroid scaffold modification to develop new selective mPRs ligands are proposed. • Two new mPRs ligands with unique selectivity were found. Progesterone modulates many processes in the body, acting through nuclear receptors (nPR) in various organs and tissues. However, a number of effects are mediated by membrane progesterone receptors (mPRs), which are members of the progestin and adipoQ (PAQR) receptor family. These receptors are found in most tissues and immune cells. They are expressed in various cancer cells and appear to play an important role in the development of tumors. The role of mPRs in the development of insulin resistance and metabolic syndrome has also attracted attention. Since progesterone efficiently binds to both nPRs and mPRs, investigation of the functions of the mPRs both at the level of the whole body and at the cell level requires ligands that selectively interact with mPRs, but not with nPRs, with an affinity comparable with that of the natural hormone. The development of such ligands faces difficulties primarily due to the lack of data on the three-dimensional structure of the ligand-binding site of mPR. This review is the first attempt to summarize available data on the structures of compounds interacting with mPRs and analyze them in terms of the differences in binding to membrane and nuclear receptors. Based on the identified main structural fragments of molecules, which affect the efficiency of binding to mPRs and are responsible for the selectivity of interactions, we propose directions of modification of the steroid scaffold to create new selective mPRs ligands. [ABSTRACT FROM AUTHOR]

• Biotransformation of 6α-methyl-16α,17α-cyclohexanoprogesterone (mecigestone) and its 6-demethylated analog in rats was studied. • These 16α,17α-cyclohexane derivatives of progesterone (pregna-D'-pentaranes) metabolize like the natural hormone. • 5β-, 5α-, 3β-Hydroxy-5α-, 20-hydroxy-5α-, 3,20-dihydroxy-5α-metabolites in urine samples were identified by HPLC-MS method. • 11 Metabolite standards were synthesized. Progesterone derivatives containing the D' additional cyclohexane ring in the 16α,17α-positions of steroid core (pregna-D′-pentaranes) exhibited high in vitro and in vivo selective progestogenic activity. The assessment of their biotransformation in the body, and the identification of possible metabolites are integral parts of a potential drug studies. Here we describe the results of in vivo metabolic transformation of 6α-methyl-16α,17α-cyclohexanopregn-4-ene-3,20-dione 1 and its 6-demethylated analog 2 and identification of their metabolites in rat urine. We synthesized and fully characterized (1D and 2D NMR, HRMS) 11 possible metabolites as the standards. Then we developed the LC–MS/MS assay including sample preparation and chromatography conditions for identification of the detected metabolites of 1 and 2. The 5α- and 5β-3,20-diketo-, 3β-hydroxy-20-keto-5α-, 3-keto-20(S)-hydroxy-5α-, 3β,20(S)-dihydroxy-5α-metabolites of compounds 1 and 2 were found in rat urine samples. The starting steroids 1 and 2 , as well as both 3β,20(R)-dihydroxy metabolites were not detected in the examined biological urine samples. Thus, we demonstrate for the first time that exogenous progestines - pregna-D′-pentaranes - and endogenous progesterone follow similar metabolic pathways. Therefore, despite the presence of an additional ring D′ and the methyl group in position 6, the main enzymatic transformations are similar to those of the natural hormone. [ABSTRACT FROM AUTHOR]