Abstract
The angiotensin II (AngII) type 1 receptor (AT1R) is a key prototypical G protein-coupled receptor in cardiovascular regulation. Biased agonists activating G protein or β-arrestin pathways offer therapeutic promise, but the molecular determinants of this signaling bias and its physiological implications remain poorly understood. This study profiles AngII analogs with C-terminal Phe(8) modifications, identifies compounds 11, 12, and 29a as exhibiting differential Gα(q) activation while retaining potent β-arrestin recruitment. Notably, 12 with low levels of Gα(q) activity, enhances left ventricular ejection fraction with limited pressor responses in normotensive rats. In contrast, other analogs with variably superior Gα(q) activity do not promote inotropy. Molecular modeling suggests that the flexible side chain of 12 accesses a deep allosteric pocket within AT1R, driving its unique signaling profile. This study demonstrates that engineering AngII's C-terminus enables selective tuning of AT1R signaling to control arterial versus cardiac responses, providing strategies for developing improved cardiovascular therapeutics.