Approaches to the design of selective ligands for membrane progesterone receptor alpha

Abstract

A number of progesterone derivatives were assayed in terms of their affinity for recombinant human membrane progesterone receptor alpha (mPRα) in comparison with nuclear progesterone receptor (nPR). The 16α,17α-cycloalkane group diminished an affinity of steroids for mPRα without significant influence on affinity for nPR, thus rendering a prominent selectivity of ligands for nPR. On the contrary, substitution of methyl at C10 for ethyl or methoxy group moderately increased the affinity for mPRα and significantly lowered the affinity for nPR. A similar but even more prominent effect was observed upon substitution of the 3-oxo group for the 3-O-methoxyimino group. A significant preference towards mPRα was also rendered by the 17α-hydroxy group and additional C6-C7-double bond. The data suggest that the modes of ligand interaction with mPRα and nPR in the C3 region of the steroid molecule are different. One can speculate that combination of the above substitutions at C17, C10, C6, and C3 may give ligand(s) with high specificity towards mPRα over nPR.

The Interface of Nuclear and Membrane Steroid Signaling

“…Researchers have been hunting for selective ligands that bind with high affinity to PAQR7, but with low or no affinity to nuclear PR ( 41 , 42 , 44 , 49 ). Only 1 identified PAQR7 ligand, Org OD 02-0, was used to interrogate the physiological function of PAQR7 in vivo.…”