Investigation the functions of membrane progesterone receptors using their selective ligands

Progesterone plays a key role in reproductive processes in the female body and has effects in the central nervous system and other tissues. Progestins are widely used clinically in contraception and hormonal therapy. The classical effects of progesterone are mediated through nuclear receptors, which are ligand-dependent transcription factors. Since 2003, membrane progesterone receptors (mPRs) of the adiponectin receptor family of five subtypes have been in the spotlight. Their role in many normal and pathological processes in the body remains unclear. Determining the mechanisms of action of progesterone is complicated by the fact that activation of different types of receptors can cause opposite effects. The search for selective ligands of mPRs is an important task, since the use of such compounds makes it possible to differentiate the effects of progestins mediated by different types of receptors. The review analyzes the action of three selective ligands of mPRs, described and studied at present. One of them is widely used in international research, the other two have been identified and used in our work. The advantages and defects of these three compounds and the studies of mPRs functions conducted using them are considered. In conclusion, the prospects for creating new selective mPRs ligands are assessed, taking into account the structural features of their ligand-binding pocket. We found that the 3-keto group of progesterone and its derivatives, which is fundamentally required for binding to nuclear steroid receptors, is not important for interaction with mPRs. Our conclusion was confirmed in a study published in 2022 using modeling techniques and mutational analysis. It is this structural feature that will further serve as the basis for the development of the synthesis of compounds that are effective and selectively interact with mPRs.