Activation of the angiotensin II type I receptor by a nonpeptide agonist

The angiotensin II type I receptor (AT1R) is a G protein–coupled receptor that regulates the cardiovascular system and as a result is one of the most successful pharmacological targets for the treatment of hypertension. Within the angiotensin receptor pharmacological landscape, agonists are peptide ligands, whereas potent antagonists are predominantly small molecules. Three decades ago, a small number of nonpeptide AT1R agonists were identified. These molecules largely share a chemical scaffold with AT1R antagonists, but appeared to interact with the receptor in a manner that diverges from both antagonists and peptide agonists. Here, we revisit L-162,313, the prototype nonpeptide AT1R agonist and determine how the antagonist-like chemical scaffold acts as an agonist. L-162,313 binds similarly to AT1R antagonists, but unlike antagonists, it engages the same activation switches as peptide agonists. We map the spatial relationship required for activation of AT1R by nonpeptide agonists and used this information to design a small library of L-162,313 derivatives. These rationally designed derivatives had the expected reduced or enhanced potency based on the structural basis for activation. Our data resolve a long-standing pharmacological mystery and provide a foundation for generating more efficacious small molecule AT1R agonists.