Many NRs have multiple subtypes that possess distinct expression patterns and that regulate distinct target genes. Antagonists generated through the addition of bulky side chains to agonist scaffolds are limited to being antagonistic on one or more subtypes of a particular NR. The passive antagonism mechanism, as revealed in our studies through direct comparison of the two THC-ER LBD complexes, suggests a new approach to achieving NR antagonism. Compounds could be designed to selectively stabilize the inactive conformations of certain NR subtypes and the active conformations of others. Such ligands are likely to exert novel biological and therapeutic effects.