Selective ligands of membrane progesterone receptors as a key to studying their biological functions in vitro and in vivo.

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.