16-ALPHA-SUBSTITUTED ANALOGS OF THE ANTIPROGESTIN RU486 INDUCE A UNIQUE CONFORMATION IN THE HUMAN PROGESTERONE-RECEPTOR RESULTING IN MIXED AGONIST ACTIVITY

Previously, we have shown that agonists and antagonists interact with distinct, though overlapping regions within the human progesterone rec eptor (hPR) resulting in the formation of structurally different compl exes. Thus, a link was established between the structure of a ligand-r eceptor complex and biological activity. In this study, we have utiliz ed a series of in vitro assays with which to study hPR pharmacology an d have identified a third class of hPR ligands that induce a receptor conformation which is distinct from that induced by agonists or antago nists, Importantly, when assayed on PR-responsive target genes these c ompounds were shown to exhibit partial agonist activity; an activity t hat was influenced by cell context. Thus, as has been shown previously for estrogen receptor, the overall structure of the ligand-receptor c omplex is influenced by the nature of the ligand, It appears, therefor e, that the observed differences in the activity of some PR and estrog en receptor ligands reflect the ability of the cellular transcription machinery to discriminate between the structurally different complexes that result following ligand interaction, These data support the incr easingly favored hypothesis that different ligands can interact with d ifferent regions within the hormone binding domains of steroid hormone receptors resulting in different biologies.