Studying the Functions of Membrane Progesterone Receptors via Selective Ligands

Progesterone plays a key role in reproductive processes inthe female body and exerts its effects in the central nervous systemand other tissues. Progestins are widely used clinically in contraceptionand hormonal therapy. The classical effects of progesterone aremediated through nuclear receptors, which are ligand-dependent transcriptionfactors. Since 2003, membrane progesterone receptors (mPRs) of the adiponectinreceptor family comprising five subtypes have been in the spotlight.Their role in many normal and pathological processes in the bodyremains unclear. Determining the mechanisms of action of progesteroneis complicated by the fact that activation of different types ofreceptors can cause opposite effects. The search for selective ligandsof mPRs is an important task, since the use of such compounds enablesdifferentiating the effects of progestins mediated by differenttypes of receptors. The review analyzes the action of three selectiveligands of mPRs, characterized to date. One of them is widely usedin international research, the other two have been identified andused in our work. The benefits and drawbacks of these three compounds,as well as the studies of mPR functions performed using them, areaddressed. The prospects for creating new selective mPR ligandsare assessed with consideration to the structural features of theirligand-binding pocket. We found that the 3-keto group of progesteroneand its derivatives, fundamentally essential for binding to nuclearsteroid receptors, is not essential for the interaction with mPRs.Our finding has been confirmed in a 2022 study using modeling techniquesand mutational analysis. It is this structural feature that willfurther serve as the basis for the development of the synthesisof compounds that effectively and selectively interact with mPRs.