What makes a good antagonist: Lessons learned from the estrogen and aryl hydrocarbon receptors

Traditionally, ligands of receptors have been classified as agonists, partial agonists, or antagonists. Study of the estrogen receptor, however, introduced the field of pharmacology to the concept of selective modulators that varied in their ability to either activate or inhibit the receptor. The mechanisms underlying these events were mapped to their unique positions within the ligand-binding cavity of the estrogen receptor and their interactions with key amino acid residues residing within this pocket. Building on these lessons, selective aryl hydrocarbon receptor modulators are currently being developed to finely tune the activities of the aryl hydrocarbon receptor and inhibit disease-modifying processes. These ongoing lessons will challenge modern pharmacologists to develop new tools and approaches for predicting the ultimate pharmacological effects of these emerging therapeutics.